ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2090G>A (p.Cys697Tyr) (rs63750398)

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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 RCV000167253 SCV000218093 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Color RCV000167253 SCV000690045 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490613 SCV000579295 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.987
Invitae RCV000817438 SCV000957998 likely pathogenic Hereditary nonpolyposis colon cancer 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 697 of the MSH2 protein (p.Cys697Tyr). 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 individuals in the Leiden Open-source Variation Database (PMID: 21520333), and an individual undergoing testing for Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 187518). Experimental studies in mouse embryonic stem cells have shown that this missense change causes low MSH2 protein levels as compared to wild-type and deficient mismatch repair activity (PMID: 26951660). Based on a multifactorial likelihood algorithm using genetic/in silico/statistical/segregation data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Variants that disrupt the p.Cys697 amino acid residue in MSH2 have been observed in affected individuals (PMID: 21239990, 17101317, Invitae). This suggests that it is a clinically significant residue, and that other 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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