ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.997T>C (p.Cys333Arg) (rs63750468)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491354 SCV000580566 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-29 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000076777 SCV000259666 likely pathogenic Lynch syndrome 2016-06-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 333 of the MSH2 protein (p.Cys333Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases. It has been reported in a patient with colon cancer and the tumor from this patient displayed microsatellite instability (PMID: 11379475). ClinVar contains an entry for this variant (Variation ID: 91272). Experimental studies in yeast have shown that this missense change disrupts MSH2 stability, blocking its interaction with binding partners and suppressing mismatch repair activity (PMID: 17720936, 20176959). In addition, a similar missense change, p.Cys333Tyr, decreases MSH2 stability and mismatch repair activity (PMID: 17720936, 18951462, 21120944) and segregates with disease in two families with Lynch Syndrome (PMID: 12624141, 17101317), indicating that the Cys residue is important. In summary, this variant is absent from the population, is present in an affected individual, and disrupts MSH2 function. For these reasons, it has been classified as Likely Pathogenic.

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