ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.998G>A (p.Cys333Tyr) (rs63750828)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216069 SCV000275379 pathogenic Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
Color RCV000216069 SCV000685148 pathogenic Hereditary cancer-predisposing syndrome 2016-07-18 criteria provided, single submitter clinical testing
Counsyl RCV000076778 SCV000785938 pathogenic Lynch syndrome I 2018-01-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504544 SCV000592484 pathogenic Lynch syndrome 2017-07-06 criteria provided, single submitter clinical testing
GeneDx RCV000160579 SCV000211169 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.998G>A at the cDNA level, p.Cys333Tyr (C333Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant was observed in several individuals, with some colon tumors exhibiting microsatellite instability and/or loss of MSH2 staining by immunohistochemistry (Parc 2003, Mangold 2005, Ward 2005, Chubb 2015, Fazekas-Lavu 2017). Several yeast based functional assays have supported the deleterious nature of this variant. Gammie et al. (2007) demonstrated loss of MSH3 and MSH6 subunit interaction and nearly absent steady-state levels of MSH2. Arlow et al. (2013) showed that the equivalent variant in yeast has an increased protein turnover mediated through the ubiquitin-mediated proteasome degradation pathway. In addition, an in-vitro assay demonstrated decreased MMR efficiency compared to wild type (Ollila 2006), and this variant showed reduced MSH2 protein levels, high rates of MSI, and mismatch repair (MMR) deficiency compared to controls in a mouse embryonic stem cell model (Houlleberghs 2016). MSH2 Cys333Tyr was not observed in large population cohorts (Lek 2016). This variant is located within the Lever domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000504544 SCV000919691 pathogenic Lynch syndrome 2018-03-21 criteria provided, single submitter clinical testing Variant summary: MSH2 c.998G>A (p.Cys333Tyr) results in a non-conservative amino acid change located in the lever domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function and several publication report experimental evidence of the variant to be MMR-deficient (Ollivia_2006; Gammie_2007; Houlleberghs_2016). The variant was absent in 246232 control chromosomes. The c.998G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome. Tumors from these pts were indicated to have MSI-I and lack of MSH2 staining on IHC, consistent with a deficiency of DNA mismatch repair (Ward_2005; Fazekas-Lavu_2017; Chubb_2015; Shia_2005). These data indicate that the variant is very likely to be associated with disease. Five 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076778 SCV000107817 pathogenic Lynch syndrome I 2016-11-03 reviewed by expert panel research Satisfies class 5 criteria
Invitae RCV000630153 SCV000751109 likely pathogenic Hereditary nonpolyposis colon cancer 2018-03-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 333 of the MSH2 protein (p.Cys333Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families with Lynch syndrome or Lynch syndrome-related cancers in the literature (PMID: 12624141, 15849733, 16175654, 21642682, 28769567, 25559809, 26681312) and in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 91273). Experimental studies have shown that this missense change produces a protein product that is unstable with deficient mismatch repair (MMR) activity (PMID: 18951462, 17101317, 26951660, 17720936). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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