ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.718C>T (p.Arg240Ter) (rs63750019)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220361 SCV000276760 pathogenic Hereditary cancer-predisposing syndrome 2018-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657653 SCV000779400 pathogenic not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.718C>T at the cDNA level and p.Arg240Ter (R240X) 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. MSH6 Arg240Ter has been reported in several individuals with personal and family history of Lynch-associated cancers, with most studied tumors demonstrating loss of MSH6 on immunohistochemistry (Yan 2008, Sjursen 2010, Kovac 2011, Roberts 2013). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075028 SCV000917786 pathogenic Lynch syndrome 2018-12-20 criteria provided, single submitter clinical testing Variant summary: MSH6 c.718C>T (p.Arg240X) 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. The variant allele was found at a frequency of 4e-06 in 247068 control chromosomes (gnomAD and publication). c.718C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Yan_2008, Sjursen_2010, Chubb_2015, Kovac_2011). 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075028 SCV000108249 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000704209 SCV000833148 pathogenic Hereditary nonpolyposis colon cancer 2018-11-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg240*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63750019, ExAC 0.006%). This variant has been observed in several individuals affected with colorectal cancer or suspected of Lynch syndrome (PMID: 18307539, 28944238, 28514183). ClinVar contains an entry for this variant (Variation ID: 89559). 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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