ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.28C>T (p.Gln10Ter) (rs63751099)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076557 SCV000107586 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000804938 SCV000944877 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln10*) 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 observed in individuals and families with suspected Lynch syndrome (PMID: 15849733, 20388775). ClinVar contains an entry for this variant (Variation ID: 91055). 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 RCV000076557 SCV000967751 pathogenic Lynch syndrome 2017-12-05 criteria provided, single submitter clinical testing The p.Gln10X variant in MSH2 has been reported in 1 individual with MSH2-associa ted cancer (Mangold 2005) and was absent from large population studies. This non sense variant leads to a premature termination codon at position 10, which is pr edicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in Lynch syndrome. In addit ion, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-a pproved InSiGHT expert panel (ClinVar SCV000107586.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon absence from controls and its predicted impact on th e protein. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting.

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