Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
NM_007194.4(CHEK2):c.1100del (p.Thr367fs)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (75)
Pathogenic (75)
75 out of 100 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
100
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1100del (p.Thr367fs)
Variation ID: 128042 Accession: VCV000128042.175
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28695869 (GRCh38) [ NCBI UCSC ] 22: 29091857 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 19, 2014 Oct 3, 2026 Aug 11, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1100del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Thr367fs frameshift NM_007194.4:c.1100delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_001005735.1:c.1229del NM_001005735.2:c.1229delC frameshift NM_001005735.3:c.1229delC NP_001005735.1:p.Thr410Metfs frameshift NM_001257387.3:c.437delC NP_001244316.1:p.Thr146Metfs frameshift NM_001349956.3:c.899delC NP_001336885.1:p.Thr300Metfs frameshift NM_145862.3:c.1013delC NP_665861.1:p.Thr338Metfs frameshift NC_000022.11:g.28695869del NC_000022.10:g.29091857del NG_008150.2:g.50998del LRG_302:g.50998del LRG_302t1:c.1100del LRG_302p1:p.Thr367fs - Protein change
- T146fs, T338fs, T410fs, T300fs, T367fs
- Other names
-
NP_009125.1:p.Thr367MetfsTer15
- Canonical SPDI
- NC_000022.11:28695868:G:
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00100 ()
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00100
1000 Genomes Project 30x 0.00109
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00120
The Genome Aggregation Database (gnomAD) 0.00175
The Genome Aggregation Database (gnomAD) 0.00181
Exome Aggregation Consortium (ExAC) 0.00182
The Genome Aggregation Database (gnomAD), exomes 0.00204
- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4733 | 4795 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (16) |
criteria provided, multiple submitters, no conflicts
|
Aug 11, 2026 | RCV000005932.46 | |
| Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Nov 10, 2025 | RCV000115980.41 | |
| Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Feb 3, 2026 | RCV000123265.54 | |
| Pathogenic (22) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2026 | RCV000212447.102 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 20, 2015 | RCV000210137.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 22, 2021 | RCV000500025.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000413386.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000488416.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515188.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2019 | RCV000587467.11 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Nov 13, 2025 | RCV000591014.13 | |
| Pathogenic (2) |
criteria provided, single submitter
|
May 7, 2021 | RCV001270933.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 4, 2021 | RCV001391208.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001354431.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 19, 2021 | RCV001572630.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 26, 2021 | RCV001770086.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 9, 2025 | RCV002225332.11 | |
|
Predisposition to cancer
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 11, 2026 | RCV002291559.10 |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 28, 2023 | RCV003445511.3 | |
|
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 1, 2006 | RCV003333692.2 |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 9, 2023 | RCV002463641.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 15, 2024 | RCV003992185.3 | |
|
CHEK2-related disorder
|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 4, 2026 | RCV004528801.6 |
|
NICE approved PARP inhibitor treatment
|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 12, 2024 | RCV004691754.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 26, 2023 | RCV003388828.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 22, 2024 | RCV004760381.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 16, 2024 | RCV005025181.2 | |
|
Inherited breast cancer and ovarian cancer
|
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 19, 2025 | RCV004577323.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV005255483.2 | |
|
Inherited prostate cancer
|
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2026 | RCV005430495.5 |
| click to load more conditions click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 20, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Breast and colorectal cancer, susceptibility to |
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266067.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Observation:
7
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 40-49 years
Observation 2
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 30-39 years
Observation 3
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 50-59 years
Observation 4
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
phyllodes breast cancer (present)
Age: 50-59 years
Observation 5
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
Observation 6
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
Observation 7
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
colon cancer (present)
Age: 50-59 years
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Breast Cancer |
Clinical and Functional Genomics Group, A.C.Camargo Cancer Center
Accession: SCV000492465.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 18, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
Familial prostate cancer Bone osteosarcoma CHEK2-related cancer predisposition |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611258.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jul 25, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698761.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
show
Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 02, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499790.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 27, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV002019280.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 08, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV003933671.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Comment:
show
Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies. (less)
Observation:
2
Observation 1
Collection method: case-control
Allele origin: germline
Affected status: yes
Comment on evidence:
1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) Data … (more)
1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) Data from PMID:11967536 (less)
Observation 2
Collection method: case-control
Allele origin: germline
Affected status: yes
Comment on evidence:
Odds Ratio (OR) = 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. Data from PMID:18172190
|
|
|
Pathogenic
(Feb 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005689639.2
First in ClinVar: Feb 16, 2025 Last updated: Mar 29, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Sep 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429484.7
First in ClinVar: Aug 16, 2020 Last updated: Dec 27, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
|
Pathogenic
(Jun 09, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Colorectal cancer
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027697.2
First in ClinVar: Aug 26, 2023 Last updated: Dec 27, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Family history of cancer (present)
Sex: male
|
|
|
Pathogenic
(Oct 26, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004100720.2
First in ClinVar: Nov 04, 2023 Last updated: Dec 27, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
|
Pathogenic
(Mar 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial prostate cancer
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812116.2
First in ClinVar: Apr 15, 2024 Last updated: Dec 27, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Prostate cancer (present)
Sex: male
|
|
|
Pathogenic
(Aug 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368410.2
First in ClinVar: Oct 13, 2024 Last updated: Dec 27, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
|
Pathogenic
(Mar 24, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV007097125.2
First in ClinVar: Nov 08, 2025 Last updated: Dec 01, 2025 |
Comment:
show
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v4: 3457 heterozygote(s), 0 homozygote(s)); Loss of function is a known mechanism of disease in this gene and is associated with tumour predisposition syndrome 4 (MIM#609265); however, dominant negative is the established mechanism of disease for the common p.(Ile157Thr) variant (PMID: 15239132); This variant has been shown to be paternally inherited (by trio analysis). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Pathogenic
(Nov 26, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition |
Institute of Human Genetics, Heidelberg University
Accession: SCV007328834.1
First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026 |
Observation 1
Collection method: clinical testing
Allele origin: maternal
Affected status: no
Number of individuals with the variant: 2
Sex: female
|
|
|
Pathogenic
(Mar 13, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007448912.1
First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026 |
Comment:
show
This variant is predicted to result in loss of function through nonsense-mediated decay of the encoded transcript or premature truncation of the encoded protein in a gene in which loss of function is a known mechanism of disease (ACMG/AMP: PVS1; PMIDs:15361853, 24879340). Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMID:11719428). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:25431674, 10617473, 18172190). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 11, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Predisposition to cancer
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000891024.3
First in ClinVar: Mar 19, 2019 Last updated: Mar 14, 2026 |
Comment:
show
The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios 2-5, PMID: 18172190, 22994785). It has also been reported in multiple cancer types such as colon, prostate, gastric, kidney, and thyroid (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This variant change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 23, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer susceptibility |
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046245.3
First in ClinVar: Oct 21, 2023 Last updated: Mar 28, 2026 |
Comment:
show
This frameshifting variant in exon 11 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on two large case-control studies, the relative risk (RR) for female breast cancer associated with the c.1100del variant was 3.0 (90% CI, 2.6–3.5) (PMID: 26014596, 15122511, 23109706). In addition, a meta-analysis reported a RR of 1.88 (95% C.I. 1.29–2.73) for CHEK2 c.1100del and colorectal cancer (PMID: 23946381). This alteration has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). The c.1100del (p.Thr367MetfsTer15) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.21% (3467/1611346), including 5 homozygous individuals. Based on the available evidence, c.1100del (p.Thr367MetfsTer15) is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 13, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
(Autosomal dominant inheritance)
|
Genetics and Molecular Pathology, SA Pathology
Accession: SCV002761797.2
First in ClinVar: Dec 17, 2022 Last updated: Jul 14, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
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pathogenic
(Aug 11, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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CHEK2-related cancer predisposition
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003804673.9
First in ClinVar: Mar 04, 2023 Last updated: Sep 13, 2026 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Family history of cancer (present) , Healthy (present)
Sex: female
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Pathogenic
(Mar 10, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-Related Cancer Susceptibility
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711416.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
show
The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 4
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Pathogenic
(May 07, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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Breast and/or ovarian cancer |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043388.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(Nov 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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Familial cancer of breast |
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061638.3
First in ClinVar: Jan 22, 2022 Last updated: Aug 05, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Secondary finding: yes
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Pathogenic
(Jul 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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Colorectal cancer |
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758585.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Pathogenic
(Dec 09, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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Familial cancer of breast |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368134.4
First in ClinVar: Jul 04, 2020 Last updated: Feb 25, 2023 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: no
Observation 1
Collection method: research
Allele origin: germline
Affected status: no
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Pathogenic
(Oct 29, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806873.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
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Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Colorectal cancer
(Autosomal dominant inheritance)
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171175.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Observation: 1
Collection method: not provided
Allele origin: germline
Affected status: yes
Observation 1
Collection method: not provided
Allele origin: germline
Affected status: yes
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Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
|
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich
Accession: SCV004174265.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
tumor (present)
Comment on clinical features:
Leukemia
Age: 0-19 years
Platform type: next-gen sequencing
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Pathogenic
(Apr 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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CHEK2-related cancer predisposition |
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005043003.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
show
ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Colon cancer (present)
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Pathogenic
(Mar 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481483.3 First in ClinVar: Feb 27, 2021 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
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Pathogenic
(Apr 25, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited breast cancer and ovarian cancer
|
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005061419.1
First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Aug 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition
(Autosomal dominant inheritance)
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Department of Human Genetics, Hannover Medical School
Accession: SCV005186168.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present)
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pathogenic
(Jul 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601142.6
First in ClinVar: Sep 28, 2017 Last updated: Jan 19, 2025 |
Comment:
show
The CHEK2 c.1100del (p.Thr367Metfs*15) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer and other cancers (PMIDs: 33471991 (2021), 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). In addition, this variant has been reported to be a founder mutation in Northern European countries (PMID: 15492928 (2004)). The frequency of this variant in the general population, 0.0087 (219/25124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
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Pathogenic
(May 16, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial prostate cancer
Bone osteosarcoma CHEK2-related cancer predisposition
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Fulgent Genetics, Fulgent Genetics
Accession: SCV005663105.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 24, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
MGZ Medical Genetics Center
Accession: SCV002581843.2
First in ClinVar: Oct 15, 2022 Last updated: Dec 27, 2025
Comment:
ACMG criteria applied: PVS1, PS3_MOD, PS4_SUP
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 23
Sex: male
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Pathogenic
(Mar 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Accession: SCV006052446.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Comment:
show
PVS1, PS3, PS4_Moderate c.1100del, located in exon 11 of the CHEK2 gene, consists in the deletion of one nucleotide, causing a translational frameshift with a predicted alternate stop codon (p.(Thr367Metfs*15)). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (PVS1). The variant allele was found in 302/116902 alleles, with a filter allele frequency of 0.22% at 99% confidence, within the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing. Several case–control studies have reported OR is between 1.5 and 5.0 (2.89, PMID: 29909568)(PS4_Moderate). Experimental studies have shown lack of kinase activity (PMID: 16982735, PMID: 31050813, PMID: 11719428, PMID: 11053450, PMID: 22114986), low protein expression and protein stability (PMID: 16982735) (PS3). This variant has been identified in the following databases, ClinVar (79x as pathogenic), LOVD (25x as pathogenic, 1x as likely pathogenic, 1x as likely benign, 7x as not provided). Based on currently available information, the variant c.1100del is classified as a pathogenic variant according to ACMG guidelines. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(Mar 31, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000187220.10
First in ClinVar: Aug 06, 2014 Last updated: Jul 13, 2025 |
Comment:
show
The c.1100delC pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon (p.T367Mfs*15). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu X et al. J. Biol. Chem. 2001 Jan;276(4):2971-4). Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (The CHEK2 Breast Cancer Case-Control Consortium. Am. J. Hum. Genet. 2004 Jun;74(6):1175-82; Xiang HP et al. Eur. J. Cancer. 2011 Nov;47(17):2546-51; Weischer M et al. J. Invest. Dermatol. 2012 Feb;132(2):299-303). However, another population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch C et al. J. Clin. Oncol. 2016 Apr;34(11):1208-16). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt MK et al. J. Clin. Oncol. 2016 Aug;34(23):2750-60). This alteration has also been reported in male breast cancer cohorts (Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407; Hallamies S et al. BMC Cancer 2017 Sep;17:620), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Dec 23, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition
(Autosomal dominant inheritance)
|
Institute of Human Genetics Munich, TUM University Hospital
Accession: SCV006302811.5
First in ClinVar: Aug 03, 2025 Last updated: Sep 22, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Melanoma (present) , Macular atrophy (present)
|
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Pathogenic
(Aug 19, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited breast cancer and ovarian cancer
|
Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub
Accession: SCV006558615.1
First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Dec 29, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552006.7
First in ClinVar: Jul 23, 2022 Last updated: Jan 03, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited prostate cancer
|
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV007131331.1
First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Dec 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691834.5
First in ClinVar: Feb 19, 2018 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 5
|
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Pathogenic
(May 28, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603087.11
First in ClinVar: Sep 30, 2017 Last updated: Jan 24, 2026 |
Comment:
show
The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Feb 09, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited prostate cancer
|
Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub
Accession: SCV007299111.2
First in ClinVar: Jan 17, 2026 Last updated: Apr 12, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Jan 05, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007600751.1
First in ClinVar: Jun 06, 2026 Last updated: Jun 06, 2026 |
Comment:
show
This is a frameshift variant in the CHEK2 gene (OMIM: 604373). Pathogenic variants in this gene have been associated with autosomal dominant tumor predisposition syndrome 4 with increased susceptibility to breast, colorectal, and prostate carcinoma. This variant introduces a premature termination codon in exon 11 out of 15 and is expected to result in loss of function, which is a known disease mechanism for CHEK2 in this disorder (PMID: 35674998) (PVS1). The alteration is an established founder variant in the Northern European population (PMID: 15492928) (PS4). Women heterozygous for this variant have been described with a relatively higher risk for familial breast cancer, compared to the average woman in the general population (PMID: 18172190). The maximum allele frequency in non-founder control populations of this variant is 0.2350% (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant tumor predisposition syndrome 4 with increased susceptibility to breast, colorectal, and prostate carcinoma. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition
(Autosomal dominant inheritance)
|
University Health Network, Familial Cancer Clinic, Princess Margaret Cancer Centre
Accession: SCV007602315.1
First in ClinVar: Jun 14, 2026 Last updated: Jun 14, 2026 |
Observation:
6
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Observed in 1 individual with germline variant in CHEK2 and APC
Observation 2
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
Sex: male
Comment on evidence:
Observed in 1 individual with germline variant in CHEK2 and APC
Observation 3
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Observed in 1 individual with germline variant in CHEK2 and BRCA2
Observation 4
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Clear cell carcinoma of kidney (present)
Sex: male
Comment on evidence:
Observed in 1 individual with germline variant in BRCA1 and CHEK2
Observation 5
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Neuroendocrine neoplasm (present)
Sex: male
Comment on evidence:
Observed in 1 individual with germline variant in CHEK2 and APC
Observation 6
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Breast carcinoma (present)
Sex: female
Comment on evidence:
Observed in 1 individual with germline variant in CHEK2 and FANCC
|
|
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Pathogenic
(Nov 21, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV007681824.1
First in ClinVar: Sep 22, 2026 Last updated: Sep 22, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Zygosity: 1 Single Heterozygote
Secondary finding: yes
|
|
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Pathogenic
(Nov 14, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related disorders
|
Blueprint Genetics
Accession: SCV007879678.1
First in ClinVar: Sep 22, 2026 Last updated: Sep 22, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
Test name: More than 5 product categories
|
|
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Pathogenic
(Aug 04, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806862.5
First in ClinVar: Sep 13, 2018 Last updated: Oct 03, 2026 |
Comment:
show
The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (Variation ID: 128042). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Apr 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-Related Cancer Susceptibility |
Illumina Laboratory Services, Illumina
Accession: SCV000915968.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
show
The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jan 26, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Academic Department of Medical Genetics, University of Cambridge
Accession: SCV000992228.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Comment:
Identified as part of research study of individuals with multiple primary tumours referred for genetic assessment
|
Comment:
show
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. (less)
Observation:
10
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Fibrofolliculoma (present) , Clear cell carcinoma of kidney (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 2
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Adenocarcinoma of the large intestine (present) , Endometrial carcinoma (present) , Basal cell carcinoma (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 3
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Thyroid carcinoma (present) , Neoplasm of the pancreas (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 4
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Clear cell carcinoma of kidney (present) , Lymphoma (present) , Adenocarcinoma of the large intestine (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 5
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present) , Stomach cancer (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 6
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Endometrial carcinoma (present) , Breast carcinoma (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 7
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present) , Renal cell carcinoma, papillary, 1 (present) , Neuroendocrine neoplasm (present) , Chronic myelogenous leukemia (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 8
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present) , Neoplasm of the pancreas (present)
Zygosity: 1 Homozygote
Platform type: Whole genome sequencing
Observation 9
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present)
Zygosity: 1 Single Heterozygote
Platform type: Whole genome sequencing
Observation 10
Collection method: research
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present) , Cutaneous melanoma (present)
Zygosity: 1 Single Heterozygote
Platform Type: Whole genome sequencing
|
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Pathogenic
(Jan 01, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
GeneKor MSA
Accession: SCV000821726.2
First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020 |
Comment:
show
This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Jun 14, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449028.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 7
Test name: Healthy Oregon Project
|
|
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Pathogenic
(Jun 04, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450042.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 19
|
|
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Pathogenic
(Mar 04, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000149889.15
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
show
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 11, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503454.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
Secondary finding: no
Platform type: NGS
|
|
|
Pathogenic
(Apr 19, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary breast ovarian cancer syndrome |
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002505157.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Geographic origin: South Africa
|
|
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Pathogenic
(Oct 04, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Sema4, Sema4
Accession: SCV002537022.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1100delC (p.T367MfsX15) variant is a well-known pathogenic variant associated with increased risk for breast, colorectal and prostate cancer. This variant was observed in … (more)
The CHEK2 c.1100delC (p.T367MfsX15) variant is a well-known pathogenic variant associated with increased risk for breast, colorectal and prostate cancer. This variant was observed in 219/25124 chromosomes in the Finnish population, with 1 homozygote, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variant ID 128042). Meta-analysis including 118,735 breast cancer cases and 195,807 controls indicated an increased breast cancer risk in overall populations (OR 2.89; 95% CI 2.63-3.16) (PMID: 29909568). Similar meta-analysis studies have shown a modest increase in colorectal (OR 1.88, 95% CI 1.29-2.73) and prostate (OR 1.98, 95% CI 1.23-3.18) cancer risk (PMID: 25431674, 23946381). This variant has also been found associated with an increased risk for other cancer types including thyroid and melanoma (PMID: 25583358, 21956126). This variant causes a frameshift at amino acid 367 that results in premature termination 15 amino acids downstream. At this location, this is predicted to result in absent protein (loss of function). Loss-of-function variants in CHEK2 are known to be pathogenic. Functional studies have shown that this variant displayed no kinase activity in vitro (PMID: 11719428). Based on the current evidence available, this variant is interpreted as pathogenic with reduced penetrance. (less)
|
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 02, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Mendelics
Accession: SCV000839467.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Nov 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009513.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
|
|
|
Pathogenic
(Mar 09, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Myriad Genetics, Inc.
Accession: SCV004020171.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
show
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jun 14, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited breast cancer and ovarian cancer
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005196372.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
NICE approved PARP inhibitor treatment
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005196385.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 05, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197499.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 19, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854533.3
First in ClinVar: Dec 16, 2018 Last updated: Dec 27, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Colitis (present) , Hematochezia (present) , Inflammation of the large intestine (present) , Thrombocytopenia (present)
Sex: male
Platform type: NGS
|
|
|
Pathogenic
(Oct 23, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Unknown mechanism)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447460.2
First in ClinVar: Nov 28, 2020 Last updated: Dec 27, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
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Pathogenic
(Sep 26, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast
Colorectal cancer Familial prostate cancer
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-COAGS
Accession: SCV002575018.2 First in ClinVar: Oct 01, 2022 Last updated: Apr 20, 2025 |
Observation 1
Collection method: research
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 19, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inherited prostate cancer
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV006100956.1
First in ClinVar: Jun 29, 2025 Last updated: Jun 29, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Feb 16, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV006110086.1
First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 09, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary breast ovarian cancer syndrome |
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV007334627.1
First in ClinVar: Jan 24, 2026 Last updated: Jan 24, 2026 |
Comment:
show
This classification follows the ACMG SVI adaptation classification scheme; We chose these criteria: PVS1 (very strong pathogenic): truncating variant within (c.139-1493), PS4 (strong pathogenic): OR 2.26-3.10 Stolarova 2023: OR, 2.73; 95% CI, 2.29–3.26 / Dorling 2021: OR 2.66 / Liang 2018 (in Stolarova 2023?): OR 2.89 (95% CI= 2.63-3.16) / Couch 2017: OR 2,31 / Schmidt 2016: OR 2.26 / Yang 2012 (in Stolarova 2023?): OR 2.75 (95% CI=2.25-3.36) / Zhang 2011: OR 3.10 , PM5 (supporting pathogenic): TF 8.7.2025: supportive of PVS1 (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: curation
Allele origin: germline
Affected status: not provided
|
|
|
Pathogenic
(Feb 03, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial cancer of breast |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166572.17
First in ClinVar: Jun 15, 2014 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 03, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292118.7
First in ClinVar: Jul 08, 2016 Last updated: Feb 15, 2026 |
Comment:
show
This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Pathogenic
(Nov 10, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Praxis Für Humangenetik, Biosciencia MVZ Labor Saar
Accession: SCV007539506.1
First in ClinVar: Apr 12, 2026 Last updated: Apr 12, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Sep 17, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
CHEK2-related cancer predisposition |
3billion
Accession: SCV007608767.1
First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026 |
Comment:
show
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.1.0 dataset and therefore considered benign. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000128042 /PMID: 10617473). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: exome sequencing
|
|
|
Pathogenic
(Jun 01, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245712.37
First in ClinVar: May 12, 2020 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 121
|
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Malignant tumor of breast |
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549046.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
show
The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Sep 27, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hereditary cancer-predisposing syndrome |
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV001977065.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jan 20, 2016)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial cancer of breast |
Counsyl
Accession: SCV000488123.3
First in ClinVar: Jul 01, 2016 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
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Pathogenic
(Aug 19, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast carcinoma |
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001792259.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
show
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Age: 30-39 years
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806916.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Study: VKGL Data-share Consensus
Accession: SCV001906450.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV001932166.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001954678.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001974642.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jul 26, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Bone osteosarcoma |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011794.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 26, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial cancer of breast |
BRCAlab, Lund University
Accession: SCV002588975.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 22, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast cancer, susceptibility to |
Genetic Services Laboratory, University of Chicago
Accession: SCV002070848.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
show
DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 01, 2006)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL |
OMIM
Accession: SCV000026114.4
First in ClinVar: Apr 04, 2013 Last updated: Feb 07, 2021 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide … (more)
In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature termination in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170). Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families thought to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals. Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men. In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women. Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer, 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men. Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer (see 114500) cases, which the authors called HBCC. The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene. To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotyped 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer. Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival. Johnson et al. (2005) found that relatives of bilateral breast cancer cases who were wildtype for CHEK2 had 3 times the population risk of female breast cancer, twice the risk of prostate cancer, and a large excess of male breast cancer. Relatives of those who were carriers of CHEK2*1100delC had an even higher risk of breast cancer and prostate cancer. The results were interpreted as indicating a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. They suggested that bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast cancer genes. Cybulski et al. (2006) identified the 1100delC mutation in 14 (0.8%) of 1,864 Polish men with prostate cancer, in 3 (1.2%) of 249 Polish men with familial prostate cancer, and in 12 (0.2%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 5.6 for familial prostate cancer in carriers of the 1-bp deletion. The authors determined that it is a founder mutation. Muranen et al. (2017) genotyped 39,139 breast cancer patients (of whom 624 were 1100delC carriers) and 40,063 healthy controls (of whom 224 were 1100delC carriers) from 32 Breast Cancer Association Consortium studies and analyzed the combined risk effects of CHEK2-1100delC and 77 common variants as a polygenic risk score (PRS) and pairwise interactions. The PRS conferred odds ratios of 1.59 (95% CI, 1.21-2.09) per standard deviation for breast cancer for CHEK2-1100delC carriers and 1.58 (1.55-1.62) for noncarriers. There was no evidence of deviation for the multiplicative model. The OR for the highest quintile was 2.03 (0.86-4.78), placing them in the high-risk category, and the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk at the population average. Breen et al. (2022) found that heterozygotes for the c.1100delC variant had an individual risk of colorectal cancer of 0.39% by age 40 to 45 years and thus recommended decreasing their age to initiate routine colonoscopy to age 40. (less)
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|
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Pathogenic
(Jul 24, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast carcinoma |
Pathway Genomics
Accession: SCV000189922.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 14, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hereditary cancer-predisposing syndrome |
True Health Diagnostics
Accession: SCV000787999.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jun 11, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Breast and/or ovarian cancer |
CZECANCA consortium
Accession: SCV001451737.1
First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
|
|
|
Pathogenic
(Mar 04, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Carcinoma of pancreas |
CZECANCA consortium
Accession: SCV001593124.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
Observation 1
Collection method: case-control
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798054.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743466.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 24, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CHEK2-related cancer predisposition |
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004171570.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Leiomyosarcoma
Breast neoplasm (Autosomal dominant inheritance)
|
Genome Sciences Centre, British Columbia Cancer Agency
Accession: SCV000574565.2
First in ClinVar: May 12, 2017 Last updated: Dec 27, 2025 |
Comment:
show
Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
|
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Pathogenic
(Jul 28, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Ovarian cancer |
Diagnostics Centre, Carl Von Ossietzky University Oldenburg
Accession: SCV004174182.2
First in ClinVar: Dec 09, 2023 Last updated: Dec 27, 2025 |
Comment:
show
The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Age: 50-59 years
Sex: female
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
not provided |
GenomeConnect, ClinGen
Accession: SCV000607207.3
First in ClinVar: Oct 16, 2017 Last updated: Dec 27, 2025 |
Comment:
show
Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Observation:
3
Observation 1
Collection method: phenotyping only
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Myopia (disease) (present) , Seizures (present) , Bleeding with minor or no trauma (present) , Epistaxis (present) , Abnormality of leukocytes (present) , Bruising susceptibility (present) , Breast carcinoma (present) , Abnormality of blood and blood-forming tissues (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Platform type: Gene Panel Sequencing
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-03-04
Testing laboratory interpretation: Pathogenic
Observation 2
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Myopia (disease) (present)
Age: 40-49 years
Sex: female
Platform type: Gene Panel Sequencing
Method: Sanger Sequencing
Testing laboratory: Color Diagnostics, LLC DBA Color Health
Date variant was reported to submitter: 2016-10-11
Testing laboratory interpretation: Pathogenic
Observation 3
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Hyperthyroidism (present) , Abnormality of the hair (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of coordination (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Delusions (present) , Hallucinations (present) , Obsessive-compulsive behavior (present) , Short attention span (present) , Atrophic scars (present) , Hyperpigmentation of the skin (present) , Hypopigmentation of the skin (present) , Cutaneous photosensitivity (present) , Thickened skin (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the foot (present) , Abnormality of muscle physiology (present) , Arrhythmia (present) , Abnormal EKG (present) , Abnormal pattern of respiration (present) , Abnormality of the stomach (present) , Abnormality of the liver (present) , Abnormality of the intestine (present) , Abnormality of the large intestine (present) , Abnormality of urine homeostasis (present) , Persistent bleeding after trauma (present) , Abnormality of thrombocytes (present) , Abnormality of erythrocytes (present) , Periodontitis (present)
Age: 40-49 years
Sex: female
Platform Type: Gene Panel Sequencing
Testing laboratory: Color Diagnostics, LLC DBA Color Health
Date variant was reported to submitter: 2019-12-09
Testing laboratory interpretation: Pathogenic
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
CHEK2-related cancer predisposition |
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749628.3
First in ClinVar: Jul 18, 2021 Last updated: Mar 21, 2026 |
Observation:
23
Observation 1
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Family history (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2017-12-20
Testing laboratory interpretation: Pathogenic
Observation 2
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Family history of cancer (present) , Intestinal polyp (present)
Zygosity: 1 Single Heterozygote
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Myriad Genetics, Inc.
Date variant was reported to submitter: 2016-12-16
Testing laboratory interpretation: Pathogenic
Observation 3
Collection method: phenotyping only
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormality of the cardiovascular system (present) , Bleeding with minor or no trauma (present) , Bruising susceptibility (present) , Epistaxis (present) , Abnormality of thrombocytes (present) , Abnormal erythrocyte morphology (present) , Seizure (present)
Indication for testing: Diagnostic
Zygosity: 1 Compound Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-03-04
Testing laboratory interpretation: Pathogenic
Observation 4
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal intestine morphology (present) , Hyperthyroidism (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Counsyl
Date variant was reported to submitter: 2017-09-11
Testing laboratory interpretation: Pathogenic
Observation 5
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Tinnitus (present) , Asthma (present) , Type 2 diabetes mellitus (present) , Anxiety (present) , Depression (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2016-02-22
Testing laboratory interpretation: Pathogenic
Observation 6
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Family history (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2018-06-13
Testing laboratory interpretation: Pathogenic
Observation 7
Collection method: phenotyping only
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Abnormality of eye movement (present) , Myopia (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2021-07-01
Testing laboratory interpretation: Pathogenic
Observation 8
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2018-12-03
Testing laboratory interpretation: Pathogenic
Observation 9
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2019-03-11
Testing laboratory interpretation: Pathogenic
Observation 10
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Hypermetropia (present) , Myopia (present) , Goiter (present) , Maternal teratogenic exposure (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2019-05-01
Testing laboratory interpretation: Pathogenic
Observation 11
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Asthma (present) , Decreased pulmonary function (present) , Recurrent infections (present) , Abnormality of reproductive system physiology (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 40-49 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2019-05-27
Testing laboratory interpretation: Pathogenic
Observation 12
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Family history of cancer (present) , Thyroid gland carcinoma (present) , Non-Hodgkin lymphoma (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2019-12-27
Testing laboratory interpretation: Pathogenic
Observation 13
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Hypermetropia (present) , Abnormal lens morphology (present) , Anxiety (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2019-06-07
Testing laboratory interpretation: Pathogenic
Observation 14
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Hyperthyroidism (present) , Seizure (present) , Pregnancy history (present) , Premature birth (present)
Indication for testing: Presymptomatic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2020-01-23
Testing laboratory interpretation: Pathogenic
Observation 15
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Family history of cancer (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: female
Method: Familial/Targeted Variant Analysis
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2020-09-02
Testing laboratory interpretation: Pathogenic
Observation 16
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Vertigo (present) , Tinnitus (present) , Hyperthyroidism (present)
Indication for testing: General Interest
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2021-02-25
Testing laboratory interpretation: Pathogenic
Observation 17
Collection method: phenotyping only
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Obesity (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 70-79 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2021-04-16
Testing laboratory interpretation: Pathogenic
Observation 18
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Bruising susceptibility (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) , Abnormal appendicular muscle morphology (present) , Hyperthyroidism (present) , Abnormality of the nervous system (present) , Abnormality of coordination (present) , Hypertonia (present) , Memory impairment (present) , Anxiety (present) , Depression (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2020-11-30
Testing laboratory interpretation: Pathogenic
Observation 19
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Vertigo (present) , Tinnitus (present) , Hyperpigmentation of the skin (present) , Hypopigmentation of the skin (present) , Vascular dilatation (present) , Hypercholesterolemia (present) , Abnormality of the bladder (present) , Abnormality of urine homeostasis (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 70-79 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2021-09-17
Testing laboratory interpretation: Pathogenic
Observation 20
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Hypermetropia (present) , Abnormal lens morphology (present) , Hypercholesterolemia (present) , Abnormal erythrocyte morphology (present) , Abnormality of the bladder (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 70-79 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2021-12-15
Testing laboratory interpretation: Pathogenic
Observation 21
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormal intestine morphology (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2022-04-06
Testing laboratory interpretation: Pathogenic
Observation 22
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormal lens morphology (present) , Myopia (present) , Abnormal retinal morphology (present) , Asthma (present) , Anxiety (present) , Depression (present) , Maternal teratogenic exposure (present) , Premature birth (present)
Indication for testing: Diagnostic
Zygosity: 1 Single Heterozygote
Age: 60-69 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2022-07-11
Testing laboratory interpretation: Pathogenic
Observation 23
Collection method: phenotyping only
Allele origin: unknown
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Abnormal renal physiology (present) , Anxiety (present) , Depression (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , Premature birth (present)
Indication for testing: Family Testing
Zygosity: 1 Single Heterozygote
Age: 20-29 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp
Date variant was reported to submitter: 2022-09-27
Testing laboratory interpretation: Pathogenic
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Uncertain significance
(-)
N
Not contributing to aggregate classification
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Flagged submission
flagged submission
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Astrocytoma |
Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston
Accession: SCV000692550.2
First in ClinVar: Apr 02, 2018 Last updated: Aug 03, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Comment on evidence:
"Uncertain function" was previously submitted as the functional consequence for NM_007194.3:c.1100delC, but without providing the result of a functional assay.
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies.
Comment:
PVS1; PS4
Comment:
Criteria applied: PVS1,PS3,PS4_MOD
Comment:
Criteria applied: PVS1,PS3,PS4,PM2_SUP
Comment:
Criteria applied: PVS1,PS3,PS4
Comment:
Criteria applied: PVS1,PS3,PS4_MOD
Comment:
Criteria applied: PVS1,PS3,PM1
Comment:
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v4: 3457 heterozygote(s), 0 homozygote(s)); Loss of function is a known mechanism of disease in this gene and is associated with tumour predisposition syndrome 4 (MIM#609265); however, dominant negative is the established mechanism of disease for the common p.(Ile157Thr) variant (PMID: 15239132); This variant has been shown to be paternally inherited (by trio analysis).
Comment:
PVS1, PS3_MOD, PS4_SUP
Comment:
This variant is predicted to result in loss of function through nonsense-mediated decay of the encoded transcript or premature truncation of the encoded protein in a gene in which loss of function is a known mechanism of disease (ACMG/AMP: PVS1; PMIDs:15361853, 24879340). Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMID:11719428). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:25431674, 10617473, 18172190).
Comment:
The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay. This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios 2-5, PMID: 18172190, 22994785). It has also been reported in multiple cancer types such as colon, prostate, gastric, kidney, and thyroid (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This variant change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
This frameshifting variant in exon 11 of 15 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on two large case-control studies, the relative risk (RR) for female breast cancer associated with the c.1100del variant was 3.0 (90% CI, 2.6–3.5) (PMID: 26014596, 15122511, 23109706). In addition, a meta-analysis reported a RR of 1.88 (95% C.I. 1.29–2.73) for CHEK2 c.1100del and colorectal cancer (PMID: 23946381). This alteration has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). The c.1100del (p.Thr367MetfsTer15) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.21% (3467/1611346), including 5 homozygous individuals. Based on the available evidence, c.1100del (p.Thr367MetfsTer15) is classified as Pathogenic.
Comment:
Criteria applied: PVS1,PS4,PM5_SUP
Comment:
The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers.
Comment:
PVS1, PS4, PS3
Comment:
ACMG criteria used to clasify this variant: PVS1, PS3, PS4
Comment:
PVS1, PS3, PS4_STR, BS1
Comment:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong
Comment:
ACMG/AMP, PVS1, PM2, PP5
Comment:
ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state
Comment:
PVS1,PS4
Comment:
The CHEK2 c.1100del (p.Thr367Metfs*15) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer and other cancers (PMIDs: 33471991 (2021), 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). In addition, this variant has been reported to be a founder mutation in Northern European countries (PMID: 15492928 (2004)). The frequency of this variant in the general population, 0.0087 (219/25124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
PVS1, PS3, PS4_Moderate c.1100del, located in exon 11 of the CHEK2 gene, consists in the deletion of one nucleotide, causing a translational frameshift with a predicted alternate stop codon (p.(Thr367Metfs*15)). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay (PVS1). The variant allele was found in 302/116902 alleles, with a filter allele frequency of 0.22% at 99% confidence, within the gnomAD v2.1.1 database (European non-Finnish non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing. Several case–control studies have reported OR is between 1.5 and 5.0 (2.89, PMID: 29909568)(PS4_Moderate). Experimental studies have shown lack of kinase activity (PMID: 16982735, PMID: 31050813, PMID: 11719428, PMID: 11053450, PMID: 22114986), low protein expression and protein stability (PMID: 16982735) (PS3). This variant has been identified in the following databases, ClinVar (79x as pathogenic), LOVD (25x as pathogenic, 1x as likely pathogenic, 1x as likely benign, 7x as not provided). Based on currently available information, the variant c.1100del is classified as a pathogenic variant according to ACMG guidelines.
Comment:
The c.1100delC pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon (p.T367Mfs*15). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu X et al. J. Biol. Chem. 2001 Jan;276(4):2971-4). Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (The CHEK2 Breast Cancer Case-Control Consortium. Am. J. Hum. Genet. 2004 Jun;74(6):1175-82; Xiang HP et al. Eur. J. Cancer. 2011 Nov;47(17):2546-51; Weischer M et al. J. Invest. Dermatol. 2012 Feb;132(2):299-303). However, another population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch C et al. J. Clin. Oncol. 2016 Apr;34(11):1208-16). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt MK et al. J. Clin. Oncol. 2016 Aug;34(23):2750-60). This alteration has also been reported in male breast cancer cohorts (Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407; Hallamies S et al. BMC Cancer 2017 Sep;17:620), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
PS4_strong, PVS1_very-strong
Comment:
PVS1,PS4,PM5_Supporting
Comment:
PP5, PS4_moderate, PVS1
Comment:
The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615.
Comment:
PS4_strong, PVS1_very-strong
Comment:
This is a frameshift variant in the CHEK2 gene (OMIM: 604373). Pathogenic variants in this gene have been associated with autosomal dominant tumor predisposition syndrome 4 with increased susceptibility to breast, colorectal, and prostate carcinoma. This variant introduces a premature termination codon in exon 11 out of 15 and is expected to result in loss of function, which is a known disease mechanism for CHEK2 in this disorder (PMID: 35674998) (PVS1). The alteration is an established founder variant in the Northern European population (PMID: 15492928) (PS4). Women heterozygous for this variant have been described with a relatively higher risk for familial breast cancer, compared to the average woman in the general population (PMID: 18172190). The maximum allele frequency in non-founder control populations of this variant is 0.2350% (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant tumor predisposition syndrome 4 with increased susceptibility to breast, colorectal, and prostate carcinoma.
Comment:
ACMG criteria applied: PS4, PVS1, PP1_Strong
Comment:
The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (Variation ID: 128042). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic.
Comment:
The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Comment:
This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042).
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
PVS1,PS4
Comment:
PVS1,PS4
Comment:
PVS1,PS4,PM5_Supporting
Comment:
This classification follows the ACMG SVI adaptation classification scheme; We chose these criteria: PVS1 (very strong pathogenic): truncating variant within (c.139-1493), PS4 (strong pathogenic): OR 2.26-3.10 Stolarova 2023: OR, 2.73; 95% CI, 2.29–3.26 / Dorling 2021: OR 2.66 / Liang 2018 (in Stolarova 2023?): OR 2.89 (95% CI= 2.63-3.16) / Couch 2017: OR 2,31 / Schmidt 2016: OR 2.26 / Yang 2012 (in Stolarova 2023?): OR 2.75 (95% CI=2.25-3.36) / Zhang 2011: OR 3.10 , PM5 (supporting pathogenic): TF 8.7.2025: supportive of PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
PVS1, PS3
Comment:
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.1.0 dataset and therefore considered benign. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000128042 /PMID: 10617473). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
CHEK2: PVS1, PP1:Strong, PS4:Moderate
Comment:
The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Comment:
DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619).
Comment:
Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer.
Comment:
The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic.
Comment:
Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. | Stolarova L | Clinical cancer research : an official journal of the American Association for Cancer Research | 2023 | PMID: 37449874 |
| A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children. | Friedrich UA | Genetics in medicine : official journal of the American College of Medical Genetics | 2023 | PMID: 37149759 |
| Detection of pathogenic variants in breast cancer susceptibility genes in bilateral breast cancer. | Evans DG | Journal of medical genetics | 2023 | PMID: 37055167 |
| Comprehensive analysis of germline drivers in endometrial cancer. | Gordhandas S | Journal of the National Cancer Institute | 2023 | PMID: 36744932 |
| Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer. | Cheng HH | JCO precision oncology | 2023 | PMID: 36623239 |
| An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes. | Breen KE | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 36222830 |
| Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies. | Stubbins RJ | Current hematologic malignancy reports | 2022 | PMID: 35674998 |
| The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. | de Oliveira JM | European journal of human genetics : EJHG | 2022 | PMID: 35534704 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Skin cancer risk in CHEK2 mutation carriers. | Bui AN | Journal of the European Academy of Dermatology and Venereology : JEADV | 2021 | PMID: 32531112 |
| Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. | Sutcliffe EG | Cancer genetics | 2020 | PMID: 32805687 |
| Clustering of known low and moderate risk alleles rather than a novel recessive high-risk gene in non-BRCA1/2 sib trios affected with breast cancer. | Hilbers FS | International journal of cancer | 2020 | PMID: 32383162 |
| Bilateral Paget's Disease of the Breast in a Patient with CHEK2 Mutation. | Owusu-Brackett N | European journal of breast health | 2020 | PMID: 32285038 |
| Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer. | Reiner AS | Journal of the National Cancer Institute | 2020 | PMID: 32119081 |
| High risk of breast cancer in women with biallelic pathogenic variants in CHEK2. | Rainville I | Breast cancer research and treatment | 2020 | PMID: 31993860 |
| One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene. | Fostira F | Journal of medical genetics | 2020 | PMID: 31300551 |
| Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts. | Zhan W | Pancreas | 2018 | PMID: 30113427 |
| Association Between CHEK2*1100delC and Breast Cancer: A Systematic Review and Meta-Analysis. | Liang M | Molecular diagnosis & therapy | 2018 | PMID: 29909568 |
| Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. | Hauke J | Cancer medicine | 2018 | PMID: 29522266 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer. | Diets IJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2018 | PMID: 29351919 |
| Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication. | Pelttari LM | Clinical genetics | 2018 | PMID: 28802053 |
| CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population. | Hallamies S | BMC cancer | 2017 | PMID: 28874143 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| Colorectal cancer risk associated with the CHEK2 1100delC variant. | Katona BW | European journal of cancer (Oxford, England : 1990) | 2017 | PMID: 28734145 |
| Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women. | Walsh T | JAMA oncology | 2017 | PMID: 28727877 |
| Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma. | Thibodeau ML | Cold Spring Harbor molecular case studies | 2017 | PMID: 28514723 |
| Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. | Rummel SK | Breast cancer research and treatment | 2017 | PMID: 28503720 |
| Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome. | Hansen MF | Clinical genetics | 2017 | PMID: 28195393 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. | Ghazani AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125075 |
| Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel. | Moran O | Breast cancer research and treatment | 2017 | PMID: 27798748 |
| Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. | Muranen TA | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27711073 |
| Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. | Leedom TP | Cancer genetics | 2016 | PMID: 27751358 |
| Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. | Pritchard CC | The New England journal of medicine | 2016 | PMID: 27433846 |
| Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. | Schmidt MK | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27269948 |
| Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil. | Palmero EI | Genetics and molecular biology | 2016 | PMID: 27223485 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings. | Seifert BA | Clinical cancer research : an official journal of the American Association for Cancer Research | 2016 | PMID: 27083775 |
| Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
| Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. | Näslund-Koch C | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26884562 |
| Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. | Parsons DW | JAMA oncology | 2016 | PMID: 26822237 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. | Churpek JE | Cancer | 2016 | PMID: 26641009 |
| The germline mutations of the CHEK2 gene are associated with an increased risk of polycythaemia vera. | Janiszewska H | British journal of haematology | 2016 | PMID: 26084796 |
| CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. | Wang Y | International journal of clinical and experimental medicine | 2015 | PMID: 26629066 |
| Gene-panel sequencing and the prediction of breast-cancer risk. | Easton DF | The New England journal of medicine | 2015 | PMID: 26014596 |
| CHEK2 mutations and the risk of papillary thyroid cancer. | Siołek M | International journal of cancer | 2015 | PMID: 25583358 |
| CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. | Hale V | Prostate cancer | 2014 | PMID: 25431674 |
| Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. | Ow GS | Cell cycle (Georgetown, Tex.) | 2014 | PMID: 24879340 |
| A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. | Bąk A | Hereditary cancer in clinical practice | 2014 | PMID: 24713400 |
| Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. | Ma X | Gut | 2014 | PMID: 23946381 |
| CHEK2*1100delC homozygosity in the Netherlands--prevalence and risk of breast and lung cancer. | Huijts PE | European journal of human genetics : EJHG | 2014 | PMID: 23652375 |
| BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. | Pennington KP | Cancer | 2013 | PMID: 22811390 |
| CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. | Weischer M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 23109706 |
| CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls. | Yang Y | Asian Pacific journal of cancer prevention : APJCP | 2012 | PMID: 22994785 |
| Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
| CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. | Weischer M | The Journal of investigative dermatology | 2012 | PMID: 21956126 |
| CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. | Adank MA | Journal of medical genetics | 2011 | PMID: 22058428 |
| Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
| Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. | Cybulski C | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21876083 |
| Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. | Xiang HP | European journal of cancer (Oxford, England : 1990) | 2011 | PMID: 21807500 |
| Li-fraumeni syndrome. | Malkin D | Genes & cancer | 2011 | PMID: 21779515 |
| A novel germline CHEK2 deletion truncating the kinase domain identified in a French family with high-risk of breast/ovarian cancer. | Escudie P | Breast cancer research and treatment | 2010 | PMID: 19768534 |
| Mice with the CHEK2*1100delC SNP are predisposed to cancer with a strong gender bias. | Bahassi el M | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19805189 |
| The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype. | Ruijs MW | Hereditary cancer in clinical practice | 2009 | PMID: 19338683 |
| CHEK2 1100delC and male breast cancer in the Netherlands. | Wasielewski M | Breast cancer research and treatment | 2009 | PMID: 18759107 |
| CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. | Weischer M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18172190 |
| Increased risk of breast cancer associated with CHEK2*1100delC. | Weischer M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2007 | PMID: 16880452 |
| A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. | Cybulski C | Journal of medical genetics | 2006 | PMID: 17085682 |
| The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry. | Bernstein JL | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2006 | PMID: 16492927 |
| Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. | Johnson N | Lancet (London, England) | 2005 | PMID: 16257342 |
| Germline CHEK2*1100delC mutations in breast cancer patients with multiple primary cancers. | Huang J | Journal of medical genetics | 2004 | PMID: 15520402 |
| CHEK2 is a multiorgan cancer susceptibility gene. | Cybulski C | American journal of human genetics | 2004 | PMID: 15492928 |
| Analysis of familial male breast cancer for germline mutations in CHEK2. | Sodha N | Cancer letters | 2004 | PMID: 15488637 |
| Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. | de Bock GH | Journal of medical genetics | 2004 | PMID: 15466005 |
| Alternative splicing and mutation status of CHEK2 in stage III breast cancer. | Staalesen V | Oncogene | 2004 | PMID: 15361853 |
| CHEK2 variant I157T may be associated with increased breast cancer risk. | Kilpivaara O | International journal of cancer | 2004 | PMID: 15239132 |
| CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. | CHEK2 Breast Cancer Case-Control Consortium | American journal of human genetics | 2004 | PMID: 15122511 |
| Limited relevance of the CHEK2 gene in hereditary breast cancer. | Dufault MR | International journal of cancer | 2004 | PMID: 15095295 |
| A novel founder CHEK2 mutation is associated with increased prostate cancer risk. | Cybulski C | Cancer research | 2004 | PMID: 15087378 |
| CHEK2*1100delC and male breast cancer risk in Israel. | Ohayon T | International journal of cancer | 2004 | PMID: 14648719 |
| Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. | Neuhausen S | International journal of cancer | 2004 | PMID: 14648718 |
| CHEK2 1100delC is not a risk factor for male breast cancer population. | Syrjäkoski K | International journal of cancer | 2004 | PMID: 14648717 |
| The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. | Meijers-Heijboer H | American journal of human genetics | 2003 | PMID: 12690581 |
| Mutations in CHEK2 associated with prostate cancer risk. | Dong X | American journal of human genetics | 2003 | PMID: 12533788 |
| A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. | Vahteristo P | American journal of human genetics | 2002 | PMID: 12094328 |
| Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. | Meijers-Heijboer H | Nature genetics | 2002 | PMID: 11967536 |
| Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. | Lee SB | Cancer research | 2001 | PMID: 11719428 |
| p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. | Vahteristo P | Cancer research | 2001 | PMID: 11479205 |
| Characterization of tumor-associated Chk2 mutations. | Wu X | The Journal of biological chemistry | 2001 | PMID: 11053450 |
| Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. | Bell DW | Science (New York, N.Y.) | 1999 | PMID: 10617473 |
| Psycho-sociology of menopause and post-menopause. | van Keep PA | Frontiers of hormone research | 1975 | PMID: 1234564 |
| [The laboratory in programs for enteric infection control]. | Grados OB | Boletin de la Oficina Sanitaria Panamericana. Pan American Sanitary Bureau | 1975 | PMID: 123456 |
| https://spadahc.ciberisciii.es/variant/GRCH37/22%2029091857%20G/- | - | - | - | - |
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Text-mined citations for rs555607708 ...
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Record last updated Oct 04, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/27/2022 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad Genetics, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.