ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1489del (p.Asp497fs)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1489del (p.Asp497fs)
Variation ID: 185176 Accession: VCV000185176.37
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28689188 (GRCh38) [ NCBI UCSC ] 22: 29085176 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 27, 2017 Feb 20, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1489del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Asp497fs frameshift NM_001005735.2:c.1618del NP_001005735.1:p.Asp540fs frameshift NM_001257387.2:c.826del NP_001244316.1:p.Asp276fs frameshift NM_001349956.2:c.1288del NP_001336885.1:p.Asp430fs frameshift NM_007194.3:c.1489del NM_145862.2:c.1402del NP_665861.1:p.Asp468fs frameshift NC_000022.11:g.28689188del NC_000022.10:g.29085176del NG_008150.2:g.57679del LRG_302:g.57679del LRG_302t1:c.1489del LRG_302p1:p.Asp497fs - Protein change
- D468fs, D540fs, D276fs, D430fs, D497fs
- Other names
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- Canonical SPDI
- NC_000022.11:28689187:C:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3945 | 3999 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2022 | RCV000164545.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000226984.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 2, 2023 | RCV000482135.5 |
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
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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
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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. |
More information
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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. |
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Pathogenic
(Oct 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134157.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one … (more)
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. (less)
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Pathogenic
(Apr 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000215201.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The c.1489delG pathogenic mutation, located in coding exon 13 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1489, causing … (more)
The c.1489delG pathogenic mutation, located in coding exon 13 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.D497Ifs*16). This alteration occurs at the 3' terminus of the CHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 47 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000564878.4
First in ClinVar: Apr 27, 2017 Last updated: May 13, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 47 amino acids are replaced with 15 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 47 amino acids are replaced with 15 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with prostate cancer (Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 32832836, 32805687, 29922827, 19782031, 22419737) (less)
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Pathogenic
(Jun 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004043289.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Likely pathogenic
(Oct 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217753.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000289664.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp497Ilefs*16) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Asp497Ilefs*16) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CHEK2 protein. This variant is present in population databases (rs774175654, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185176). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV002588976.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. | Hu C | JAMA | 2018 | PMID: 29922827 |
CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? | Antoni L | Nature reviews. Cancer | 2007 | PMID: 18004398 |
Karyopherin-alpha2 protein interacts with Chk2 and contributes to its nuclear import. | Zannini L | The Journal of biological chemistry | 2003 | PMID: 12909615 |
Text-mined citations for rs774175654 ...
HelpRecord last updated Feb 28, 2024
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.