ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2194C>T (p.Arg732Ter) (rs63751127)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074726 SCV000107934 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000132226 SCV000187309 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 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 RCV000212661 SCV000211293 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.2194C>T at the cDNA level and p.Arg732Ter (R732X) at the protein level. The substitution creates a nonsense variant, changing an Arginine to a premature stop codon (CGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in several individuals with personal and/or family histories suggestive of Lynch syndrome (Plaschke 2004, Steinke 2008, Giraldez 2010, Song 2014, Lagerstedt-Robinson 2016) and is considered pathogenic.
Invitae RCV000524134 SCV000253776 pathogenic Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg732*) 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 reported in individuals with Lynch syndrome (PMID: 15483016, 18301448, 20028993), and an individual affected with ovarian cancer (PMID: 24728189). ClinVar contains an entry for this variant (Variation ID: 89262). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074726 SCV000592600 pathogenic Lynch syndrome 2015-05-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074726 SCV000711432 pathogenic Lynch syndrome 2016-03-18 criteria provided, single submitter clinical testing The p.Arg732X variant in MSH6 has been reported in at least 5 individuals with h ereditary non-polyposis colorectal cancer (HNPCC) and related tumors (Plaschke 2 004, Steinke 2008, Baglietto 2010, Giraldez 2010, Song 2014) and was absent from large population studies. This nonsense variant leads to a premature terminatio n codon at position 732, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss-of-function of the MSH6 gene is an establish disease mec hanism for Lynch syndrome. In summary, this variant meets criteria to be classif ied as pathogenic for Lynch syndrome in an autosomal dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212661 SCV000889471 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
Color RCV000132226 SCV000905454 pathogenic Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074726 SCV000919757 pathogenic Lynch syndrome 2018-09-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2194C>T (p.Arg732X) 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.2230dupG, p.Glu744fsX12; c.2503C>T, p.Gln835X; c.2731C>T , p.Arg911X). The variant allele was found at a frequency of 4.1e-06 in 245604 control chromosomes (gnomAD). The variant, c.2194C>T, has been reported in the literature in individuals affected with Lynch Syndrome (Susswein_2015, Rossi_2017, Baglietto_2010, Song_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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