ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1165C>T (p.Arg389Ter) (rs587779075)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076052 SCV000107065 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing a premature termination codon
GeneDx RCV000202008 SCV000149403 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1165C>T at the cDNA level and p.Arg389Ter (R389X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported multiple times in association with Lynch syndrome (Beck 1997, Millar 1999, Mangold 2004, Choi 2009, Chong 2009, Bonadona 2011, Chubb 2015) and is considered pathogenic.
Ambry Genetics RCV000115494 SCV000184319 pathogenic Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524332 SCV000253796 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg389*) 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 numerous individuals affected with Lynch syndrome cancers (PMID: 19459153, 10196371, 22883484, 25117503, 21642682, 15235030). ClinVar contains an entry for this variant (Variation ID: 90557). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000409481 SCV000488244 pathogenic Lynch syndrome I 2016-02-02 criteria provided, single submitter clinical testing
Color RCV000115494 SCV000537676 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076052 SCV000592489 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202008 SCV000601425 pathogenic not provided 2015-11-05 criteria provided, single submitter clinical testing
Mendelics RCV000076052 SCV000837828 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076052 SCV000917712 pathogenic Lynch syndrome 2018-07-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1165C>T (p.Arg389X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1189C>T, p.Gln397X; c.1216C>T, p.Arg406X). The variant was absent in 246248 control chromosomes (gnomAD). The variant, c.1165C>T, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Caldes_2002, Chong_2009, Pinol_2005, Casey_2005, Mangold_2005, Mongiat-Artus_2006, Wagner_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202008 SCV000257124 pathogenic not provided no assertion criteria provided research

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