ClinVar Miner

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

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000116001 SCV000186804 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Invitae RCV000198554 SCV000254925 uncertain significance Familial cancer of breast 2020-01-06 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). However, the results of a history weighting algorithm suggest that this variant does not show an association with breast cancer risk as expected for known pathogenic CHEK2 variants (external communication). 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.
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
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.
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
Genetic Services Laboratory,University of Chicago RCV000499890 SCV000594113 likely pathogenic not specified 2019-07-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212465 SCV000601155 likely pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in a single case with an otherwise positive result. Assessment of experimental evidence suggests this variant results in abnormal protein function.
GeneID Lab - Advanced Molecular Diagnostics RCV000116001 SCV000680448 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Color RCV000116001 SCV000689655 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-06 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
Counsyl RCV000198554 SCV000785095 uncertain significance Familial cancer of breast 2017-10-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212465 SCV000806869 likely pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116001 SCV000821724 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is highly conserved among species in the Protein kinase domain of the protein and there is physiochemical difference between threonine and methionine (Grantham Score 81). This variant has been described in the international literature in individuals affected with breast and endometrial cancers (PMID: 21244692, PMID: 27443514).This variant is present in mutation databases at a low frequency (rs142763740, ExAC 0.07%). The mutation database ClinVar contains entries for this variant (Variation ID: 128060). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies. (PMID: 22114986, PMID: 22419737).
Mendelics RCV000198554 SCV000839455 likely pathogenic Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212465 SCV001249408 likely pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000499890 SCV001339088 uncertain significance not specified 2020-03-26 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is benign. In addition, co-occurrences with other pathogenic variants have been internally reported (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing supporting evidence for a benign role. The variant has been observed in individuals affected with Breast, Ovarian, Colorectal, and Pancreatic cancers (Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen. However, functional studies have shown that Thr476Met disrupts CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. 17 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x) and likely pathogenic (10x). Based on the evidence outlined above, the variant was classified as uncertain significance until more definitive data becomes available.
Institute of Human Genetics, University of Leipzig Medical Center RCV000198554 SCV001429101 uncertain significance Familial cancer of breast 2018-02-23 criteria provided, single submitter clinical testing

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