ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2074G>C (p.Gly692Arg) (rs63750232)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491588 SCV000580386 pathogenic Hereditary cancer-predisposing syndrome 2017-09-20 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,Deficient protein function in appropriate functional assay(s),in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (LOD 1.5-3 = 5-9 meioses)
Color RCV000491588 SCV000908324 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076380 SCV000107407 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000821619 SCV000962388 likely pathogenic Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 692 of the MSH2 protein (p.Gly692Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 28577310), and to segregate with Lynch syndrome in a single family (PMID: 10612836). ClinVar contains an entry for this variant (Variation ID: 90878). This variant has been reported to affect MSH2 protein function (PMID: 26951660, 17720936). This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 29212164, 23454724, 12624141, 28135145, 23729658), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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