NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met) AND not provided
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000212465.49
Allele description [Variation Report for NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)]
NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)
- Gene:
- CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 22q12.1
- Genomic location:
- Preferred name:
- NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)
- Other names:
- p.T476M:ACG>ATG
- HGVS:
- NC_000022.11:g.28694066G>A
- NG_008150.2:g.52801C>T
- NM_001005735.2:c.1556C>T
- NM_001257387.2:c.764C>T
- NM_001349956.2:c.1226C>T
- NM_007194.4:c.1427C>TMANE SELECT
- NM_145862.2:c.1340C>T
- NP_001005735.1:p.Thr519Met
- NP_001244316.1:p.Thr255Met
- NP_001336885.1:p.Thr409Met
- NP_009125.1:p.Thr476Met
- NP_665861.1:p.Thr447Met
- LRG_302t1:c.1427C>T
- LRG_302:g.52801C>T
- LRG_302p1:p.Thr476Met
- NC_000022.10:g.29090054G>A
- NG_008150.1:g.52769C>T
- NM_001005735.1:c.1556C>T
- NM_007194.3:c.1427C>T
- p.T476M
This HGVS expression did not pass validation- Protein change:
- T255M
- Links:
- dbSNP: rs142763740
- NCBI 1000 Genomes Browser:
- rs142763740
- Molecular consequence:
- NM_001005735.2:c.1556C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001257387.2:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001349956.2:c.1226C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_007194.4:c.1427C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_145862.2:c.1340C>T - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 10
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000149910 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Likely pathogenic (Jan 10, 2020) | germline | clinical testing | |
SCV000601155 | Quest Diagnostics Nichols Institute San Juan Capistrano | criteria provided, single submitter (Quest Diagnostics criteria) | Uncertain significance (Jun 22, 2023) | unknown | clinical testing | PubMed (49) |
SCV001249408 | CeGaT Center for Human Genetics Tuebingen | criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) | Uncertain significance (Mar 1, 2024) | germline | clinical testing | |
SCV001447152 | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Oct 23, 2020) | germline | clinical testing | |
SCV001449986 | Clinical Genetics and Genomics, Karolinska University Hospital | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Jan 21, 2020) | germline | clinical testing | |
SCV001743206 | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus | no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV001807610 | Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus | no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV001905737 | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus
| no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV001953604 | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus
| no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV001972177 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus
| no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV002009506 | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Nov 3, 2021) | germline | clinical testing | |
SCV002022540 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Jun 30, 2022) | germline | clinical testing | |
SCV002036846 | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus
| no assertion criteria provided | Uncertain significance | germline | clinical testing | |
SCV003799997 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) | Likely pathogenic (Sep 16, 2022) | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | 10 | not provided | not provided | 1 | not provided | clinical testing |
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Girard E, Eon-Marchais S, Olaso R, Renault AL, Damiola F, Dondon MG, Barjhoux L, Goidin D, Meyer V, Le Gal D, Beauvallet J, Mebirouk N, Lonjou C, Coignard J, Marcou M, Cavaciuti E, Baulard C, Bihoreau MT, Cohen-Haguenauer O, Leroux D, Penet C, Fert-Ferrer S, et al.
Int J Cancer. 2019 Apr 15;144(8):1962-1974. doi: 10.1002/ijc.31921. Epub 2018 Nov 13.
- PMID:
- 30303537
- PMCID:
- PMC6587727
Bertelsen B, Tuxen IV, Yde CW, Gabrielaite M, Torp MH, Kinalis S, Oestrup O, Rohrberg K, Spangaard I, Santoni-Rugiu E, Wadt K, Mau-Sorensen M, Lassen U, Nielsen FC.
NPJ Genom Med. 2019;4:13. doi: 10.1038/s41525-019-0087-6.
- PMID:
- 31263571
- PMCID:
- PMC6588611
Details of each submission
From GeneDx, SCV000149910.14
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
Published functional studies demonstrate a damaging effect: most show reduced or absent kinase activity and DNA damage response (Desrichard 2011, Roeb 2012, Delimitsou 2019, Kleiblova 2019); Observed in many individuals with personal and/or family history of CHEK2-related cancers (Desrichard 2011, Le Calvez-Kelm 2011, Hu 2015, Leedom 2016, Pritzlaff 2016, Shirts 2016, Frey 2017, Isaacsson Velho 2018, Schubert 2018, Wu 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 29368341, 21244692, 29945567, 28944238, 25186627, 26845104, 22862163, 23552953, 28008555, no PMID, 10617473, 22419737, 22114986, 26787654, 26483394, 27751358, 21901162, 28495237, 27621404, 26022348, 27443514, 15095295, 29478780, 29520813, 30128536, 31050813, 30613976, 30851065, 30426508, 24595525, 30322717, 31159747, 31784482, 30303537, 31447099, 32832836, 31263571, 31948886)
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601155.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (49) |
Description
In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 32658311 (2021), 33030641 (2020), 32906215 (2020), 31050813 (2019), 30287823 (2018), 28008555 (2017), 22862163 (2012), 21244692 (2011)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 26845104 (2016)), colorectal cancer (PMIDs: 32658311 (2021), 28944238 (2017)), and prostate cancer (PMIDs: 32832836 (2020), 29520813 (2018)). This variant has also been reported in unaffected individuals (PMIDs: 32658311 (2021), 31050813 (2019), 30287823 (2018)). Additionally, experimental studies have reported conflicting results in this variant's impact on CHEK2 protein functions (PMIDs: 31050813 (2019), 30851065 (2019), 22419737 (2012)), 22114986 (2011)). The frequency of this variant in the general population, 0.0005 (62/124190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From CeGaT Center for Human Genetics Tuebingen, SCV001249408.20
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 7 | not provided | not provided | clinical testing | not provided |
Description
CHEK2: PM1, PS3:Moderate, BP4
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 7 | not provided | not provided | not provided |
From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447152.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | 1 | not provided | not provided | not provided | not provided | not provided | not provided |
From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449986.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 3 | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 3 | not provided | not provided | not provided |
From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743206.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807610.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001905737.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001953604.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972177.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009506.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Revvity Omics, Revvity, SCV002022540.3
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036846.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799997.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
The CHEK2 c.1427C>T; p.Thr476Met variant (rs142763740) is reported in numerous individuals with CHEK2-associated cancers (Classen 2013, Girard 2019, Hu 2018, Kamihara 2022, Le Calvez-Kelm 2011, Lilyquist 2017, Rizzolo 2019, Sutcliffe 2020), but is also reported in individuals without cancer suggesting reduced penetrance (Girard 2019). The overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). In vitro kinase assays and in vivo DNA damage response assays with the variant protein showed a loss of kinase activity and impaired function (Delimitsou 2019, Desrichard 2011, Kleiblova 2019, Roeb 2012). However, one CHEK2-cell based assay showed no effect of the variant on protein function (Kleiblova 2019). This variant is reported by multiple laboratories in ClinVar (Variation ID: 128060). It is found in the general population with an overall allele frequency of 0.03% (83/265178 alleles) in the Genome Aggregation Database. The threonine at codon 476 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.445). Based on the currently available information, this variant is considered to be likely pathogenic. References: Classen CF et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet. 2013 Jul;132(7):825-41. PMID: 23552953. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Girard E et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer. 2019 Apr 15;144(8):1962-1974. PMID: 30303537. Hu C et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827. Kamihara J et al. Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition. Cancer Med. 2022 Apr;11(8):1745-1752. PMID: 35174967. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. PMID: 21244692. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Rizzolo P et al. Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer. 2019 Jul 15;145(2):390-400. PMID: 30613976. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. PMID: 26484312. Sutcliffe EG et al. Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet. 2020 Aug;246-247:12-17. PMID: 32805687.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Apr 15, 2024