ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1384C>T (p.Gln462Ter) (rs876657701)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492035 SCV000580407 pathogenic Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000630030 SCV000750986 pathogenic Hereditary nonpolyposis colon cancer 2018-08-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln462*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 25872134). ClinVar contains an entry for this variant (Variation ID: 228365). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220084 SCV000271400 pathogenic Lynch syndrome 2015-10-27 criteria provided, single submitter clinical testing The p.Gln462X variant in MSH2 has not been previously reported in individuals wi th Lynch syndrome but has been reported in ClinVar by another clinical laborator y (Variation ID 228365). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 462, wh ich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established mechanism of disease for Lynch synd rome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the on the predicted impact of the variant and its absence from controls.

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