ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.862C>T (p.Gln288Ter) (rs63750097)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076738 SCV000107775 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000484173 SCV000565185 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.862C>T at the cDNA level and p.Gln288Ter (Q288X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in multiple families with Hereditary Nonpolyposis Colorectal Cancer and in at least 1 individual with Muir-Torre Syndrome, and tumor studies from some of these individuals showed microsatellite instability and loss of MSH2 protein expression (Wijnen 1995, Wijnen 1997, Kruse 1998, Pistorius 2000, Hendriks 2003, Lage 2004, Mangold 2004, Mangold 2005, Overbeek 2007, Dominquez-Valentin 2013). Based on current information, we consider this variant to be pathogenic.
Invitae RCV000528830 SCV000625475 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln288*) 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 individuals affected with Lynch syndrome (PMID: 7726159, 15849733, 12547705, 28874130), and one individual with Muir-Torre syndrome (PMID: 15235030). ClinVar contains an entry for this variant (Variation ID: 91233). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color RCV001183048 SCV001348703 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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