ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1444C>T (p.Arg482Ter) (rs63750909)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491001 SCV000580093 pathogenic Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491001 SCV000903766 pathogenic Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000410127 SCV000489704 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-11-09 criteria provided, single submitter clinical testing
GeneDx RCV000215386 SCV000279095 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1444C>T at the cDNA level and p.Arg482Ter (R482X) 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 observed in multiple individuals with Lynch syndrome-associated cancers (Hendriks 2004, Nilbert 2009, Baglietto 2010, Sjursen 2010, Therkildsen 2015, Yurgelun 2015) and in colon cancers showing absence of MSH6 protein by immunohistochemistry (Okkels 2012). We therefore consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074656 SCV000695783 pathogenic Lynch syndrome 2016-02-02 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074656 SCV000107858 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524108 SCV000261811 pathogenic Hereditary nonpolyposis colon cancer 2018-09-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 482 (p.Arg482*). 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 the literature in individuals affected with Lynch syndrome (PMID: 15236168, 20028993, 21836479, 20587412, 22495361). ClinVar contains an entry for this variant (Variation ID: 89194). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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