ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.742C>T (p.Arg248Ter) (rs63749980)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075032 SCV000108253 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524215 SCV000253781 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg248*) in the MSH6 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 observed in individual(s) with Lynch syndrome (PMID: 10508506, 18301448). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000486750 SCV000566643 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.742C>T at the cDNA level and p.Arg248Ter (R248X) 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 in at least two families with Lynch syndrome (Wijnen 1999, Hendriks 2003, Steinke 2008) and is considered pathogenic.
Ambry Genetics RCV000490932 SCV000580084 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486750 SCV001134456 pathogenic not provided 2019-03-25 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV001193103 SCV001361712 pathogenic Hereditary nonpolyposis colon cancer 2019-03-12 criteria provided, single submitter clinical testing Variant summary: MSH6 c.742C>T (p.Arg248X) 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.892C>T, p.Arg298X; c.1135_1139delAGAGA, p.Arg379X; c.1190_1191delAT, p.Tyr397fsX3). The variant was absent in 276846 control chromosomes (gnomAD). c.742C>T has been reported in the literature in individuals affected with Lynch Syndrome; analysis of tumor samples showed loss of MSH6 protein expression via immunohistochemistry and high microsatellite instability (Steinke_2008, Hendriks_2003, Wijnen_1999). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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