ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3477C>A (p.Tyr1159Ter) (rs398123231)

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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 RCV000491158 SCV000580185 pathogenic Hereditary cancer-predisposing syndrome 2018-01-08 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)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078315 SCV000110159 pathogenic not provided 2013-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781593 SCV000919761 likely pathogenic Lynch syndrome 2018-09-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3477C>A (p.Tyr1159X) 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 (e.g. p.Asp1171fsX5 and p.His1203fsX12). The variant was absent in 246160 control chromosomes (gnomAD). c.3477C>A has been reported in the literature in individuals affected with Lynch Syndrome or related tumor phenotypes (Bonadona 2011, Perez-Carbonell 2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000456684 SCV000551165 pathogenic Hereditary nonpolyposis colon cancer 2018-07-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1159*) 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 the literature in individuals affected with Lynch syndrome-associated cancers (PMID: 21642682, 21868491). ClinVar contains an entry for this variant (Variation ID: 92577). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078315 SCV000257257 pathogenic not provided no assertion criteria provided research

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