ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1035G>A (p.Trp345Ter) (rs63750396)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076005 SCV000107016 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variant introducing a premature termination codon
Ambry Genetics RCV000492045 SCV000580470 pathogenic Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000202230 SCV000779393 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1035G>A at the cDNA level and p.Trp345Ter (W345X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>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 in association with Lynch syndrome (Ponz de Leon 2004, Tang 2009, Vargas-Parra 2017) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193248 SCV001361976 pathogenic Lynch syndrome 2019-06-17 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1035G>A (p.Trp345X) 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. The variant was absent in 251438 control chromosomes. c.1035G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome or related cancer (Leon_2004, Roberts_2014, Kamiza_2015, Mu_2016, Vargas-Parra_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both 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 RCV000202230 SCV000257120 pathogenic not provided no assertion criteria provided research

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