ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2503C>T (p.Gln835Ter) (rs63751321)

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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) RCV000074750 SCV000107960 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000218020 SCV000277323 pathogenic Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000520652 SCV000617712 pathogenic not provided 2017-03-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2503C>T at the cDNA level and p.Gln835Ter (Q835X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 one individual with an MSI-high colon cancer showing loss of MSH6 protein expression by immunohistochemistry (Rahner 2007). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074750 SCV000917760 pathogenic Lynch syndrome 2018-05-11 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2503C>T (p.Gln835X) 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.2731C>T(p.Arg911X), c.2764C>T (p.Arg922X), and c.3013C>T (p.Arg1005X)). The variant was absent in 244044 control chromosomes (gnomAD). The c.2503C>T has been reported in the literature in individuals from AC families affected with Lynch Syndrome (Rhaner_2007, Steinke_2008). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001223542 SCV001395698 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-07-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln835*) 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 a family affected with Lynch syndrome (PMID: 17653898). ClinVar contains an entry for this variant (Variation ID: 89285). 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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