ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met) (rs142763740)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116001 SCV000186804 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000116001 SCV000689655 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Counsyl RCV000198554 SCV000785095 uncertain significance Familial cancer of breast 2017-10-06 criteria provided, single submitter clinical testing
GeneDx RCV000212465 SCV000149910 likely pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1427C>T at the cDNA level, p.Thr476Met (T476M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in individuals with a personal and/or family history of breast, pancreatic, or prostate cancer (Desrichard 2011, Le Calvez-Kelm 2011, Hu 2015, Leedom 2016, Pritzlaff 2016, Shirts 2016, Frey 2017, Isaacsson Velho 2018, Schubert 2018, Wu 2018). This variant was shown in an in vitro study to abolish kinase activity, and was shown in an in vivo study to impair CHEK2-mediated response to DNA damage (Desrichard 2011, Roeb 2012). A different nucleotide change (CHEK2 c.1427C>A) resulting in the same amino acid substitution was identified in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sadri 2014). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Thr476Met is located in the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider CHEK2 Thr476Met to be a likely pathogenic variant.
GeneID Lab - Advanced Molecular Diagnostics RCV000116001 SCV000680448 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116001 SCV000821724 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000499890 SCV000594113 uncertain significance not specified 2016-11-21 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000198554 SCV000778585 uncertain significance Familial cancer of breast 2018-04-16 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000259876 SCV000437713 uncertain significance Colorectal cancer 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000317389 SCV000437714 likely pathogenic Neoplasm of the breast 2016-06-14 criteria provided, single submitter clinical testing Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer.
Illumina Clinical Services Laboratory,Illumina RCV000778653 SCV000914986 likely pathogenic CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000116001 SCV000576430 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212465 SCV000698777 uncertain significance not provided 2016-10-14 criteria provided, single submitter clinical testing
Invitae RCV000198554 SCV000254925 uncertain significance Familial cancer of breast 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 476 of the CHEK2 protein (p.Thr476Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142763740, ExAC 0.07%). This variant has been reported in individuals affected with breast cancer (PMID: 21244692), endometrial cancer (PMID: 27443514), colorectal cancer (PMID: 28944238), prostate cancer (PMID: 29368341, 29520813), and in a male with breast and colon cancer (PMID: 28008555). ClinVar contains an entry for this variant (Variation ID: 128060). Experimental studies have shown that this missense change disrupts CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (PMID: 22114986, 22419737). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000198554 SCV000839455 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000212465 SCV000806869 likely pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212465 SCV000601155 likely pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210077 SCV000266166 uncertain significance Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing

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