ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.538C>T (p.Arg180Cys) (rs77130927)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588124 SCV000149933 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.538C>T at the cDNA level, p.Arg180Cys (R180C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). Also published as CHEK2 c.667C>T (p.Arg223Cys) based on an alternate transcript, this variant has been observed in several patients with breast, prostate, or ovarian cancer, but has also been seen in control populations (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017). In a large meta-analysis, evidence of association with breast cancer risk was observed for European and Asian women, with odds ratios (OR) of 1.33 and 1.16, respectively; however, the confidence intervals approached or included 1.0 (Southey 2016). Decker et al. (2017) showed no association with this variant and breast cancer in their case-control study (OR 1.26, p=0.57). Additionally, this variant was shown to have an intermediate response to DNA damage, when compared to wild-type, in yeast-based assays (Walsh 2011, Roeb 2012). CHEK2 Arg180Cys was observed at an allele frequency of 0.31% (58/18,866) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Forkhead-associated (FHA) domain (Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Arg180Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116024 SCV000185905 benign Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Intact protein function observed in appropriate functional assay(s),General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,No disease association in appropriately sized case-control study(ies)
Invitae RCV000588124 SCV000253487 likely benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490304 SCV000267255 uncertain significance Malignant tumor of prostate 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000196561 SCV000488845 uncertain significance Familial cancer of breast 2016-07-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212426 SCV000594118 uncertain significance not specified 2016-07-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212426 SCV000601172 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing
Color RCV000116024 SCV000689694 benign Hereditary cancer-predisposing syndrome 2016-02-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588124 SCV000698810 likely benign not provided 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000116024 SCV000747819 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Mendelics RCV000196561 SCV000839487 benign Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588124 SCV000889337 uncertain significance not provided 2018-04-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588124 SCV001153648 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing

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