ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1190A>G (p.Tyr397Cys) (rs63750065)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565934 SCV000673925 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000565934 SCV000903473 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-16 criteria provided, single submitter clinical testing
Counsyl RCV000662428 SCV000784881 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000656894 SCV000211275 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1190A>G at the cDNA level, p.Tyr397Cys (Y397C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). MSH6 Tyr397Cys has been observed in at least two patients with a personal and family history of colorectal cancer, with one of these colon tumors exhibiting microsatellite instability (MSI) and loss of MLH1 and PMS2 proteins (Terui 2013, Chubb 2015). MSH6 Tyr397Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Tyr397Cys is located in the mismatch binding domain and nuclear localization signals domain (Warren 2007, Kansikas 2010, Gassman 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Tyr397Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000160665 SCV000917783 uncertain significance not specified 2018-10-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1190A>G (p.Tyr397Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 245978 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1190A>G has been reported in the literature in individuals affected with colorectal cancer without strong evidence for or against causality (Terui 2013, Chubb 2015). Thus, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000206352 SCV000260423 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 397 of the MSH6 protein (p.Tyr397Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs63750065, ExAC 0.01%). This variant has been reported in individuals with colorectal cancer (PMID: 24100870, 25559809). ClinVar contains an entry for this variant (Variation ID: 182620). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). However, an algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to impact MSH6 function (PMID: 23621914). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000160665 SCV000967446 uncertain significance not specified 2018-10-16 criteria provided, single submitter clinical testing The p.Tyr397Cys variant in MSH6 has been reported in 2 individuals with colorect al cancer (Terui 2013, Chubb 2015) and has been reported by other clinical labor atories in ClinVar (Variation ID: 182620). This variant has also been identified in 2/30780 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) . Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. However, an algorithm develope d for in silico prediction of variants in MSH6 gene suggests that this variant i s likely to impact MSH6 function (Terui 2013). In summary, the clinical signific ance of the p.Tyr397Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Sup porting, PM2_Supporting.
Mendelics RCV000708864 SCV000837879 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160665 SCV000601504 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656894 SCV000889455 uncertain significance not provided 2018-06-04 criteria provided, single submitter clinical testing

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