ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2089T>C (p.Cys697Arg) (rs63750961)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076384 SCV000107411 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000076384 SCV000284136 pathogenic Lynch syndrome 2016-07-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 697 of the MSH2 protein (p.Cys697Arg). 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 (rs63750961, ExAC no frequency). This variant has been reported in individuals affected with hereditary nonpolyposis colorectal cancer (HNPCC, PMID: 10480359, 21239990, 20937110, 14970868, 10471663, 17973265, 21598002), and to segregate with HNPCC in a single family (PMID: 10612836). ClinVar contains an entry for this variant (Variation ID: 90882). Based on a multifactorial likelihood algorithm using genetic/in silico/statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816, 22949387, 22290698). Furthermore, experimental studies have shown that this variant has a deleterious impact on MSH2 protein stability and MMR function (PMID: 17720936, 12377806), but has no impact on mRNA splicing (PMID: 16395668, 18561205). This variant is located in the highly conserved adenosine triphosphate domain, which is important for the DNA mismatch repair (MMR) function of the MSH2 protein (PMID: 21239990). A different missense substitution at this codon (p.Cys697Phe) is reported to be deleterious (PMID: 18951462). This indicates that the 697 residue is important for MSH2 protein function. For these reasons, this variant has been classified as Pathogenic.

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