ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1738G>T (p.Glu580Ter) (rs63751411)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491635 SCV000580455 pathogenic Hereditary cancer-predisposing syndrome 2018-01-04 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)
GeneDx RCV000483706 SCV000568631 pathogenic not provided 2017-03-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1738G>T at the cDNA level and p.Glu580Ter (E580X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 Glu580Ter has been found to be associated with reduced mRNA expression (Casey 2005). In addition, this variant has been observed in at least one individual with a malignant mixed glioma and several individuals with personal and/or family histories of colon cancer, some of which met Amsterdam or Bethesda Lynch Syndrome criteria and whose corresponding tumors were often microsatellite unstable and/or had abnormal protein staining on immunohistochemistry (Leung 1998, Chen 1999, Mangold 2005, Jasperson 2010, Brieger 2011). Based on currently available evidence, we consider this variant to be pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785573 SCV000924145 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076261 SCV000107282 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000552781 SCV000625302 pathogenic Hereditary nonpolyposis colon cancer 2018-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu580*) 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 several individuals affected with MSH2-related disease (PMID: 9777949, 15713769, 15849733, 16216036, 21598002, 28874130). ClinVar contains an entry for this variant (Variation ID: 90763). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000483706 SCV000691906 pathogenic not provided no assertion criteria provided clinical testing

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