ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3477C>G (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
Invitae RCV000228304 SCV000283808 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-02 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). While this particular variant has not been reported in the literature, a different variant (c.3477C>A) giving rise to the same protein effect observed here (p.Tyr1159*) has been reported in the literature in a family with Lynch syndrome (PMID: 21642682). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color RCV000580568 SCV000685409 pathogenic Hereditary cancer-predisposing syndrome 2016-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000657748 SCV000779500 pathogenic not provided 2018-01-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3477C>G at the cDNA level and p.Tyr1159Ter (Y1159X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781603 SCV000919775 pathogenic Lynch syndrome 2018-11-21 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3477C>G (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 (eg. p.Asp1171fsX5, p.Arg1172fsX5, p.His1203fsX12). The variant allele was found at a frequency of 4.1e-06 in 246160 control chromosomes. c.3477C>G has not been reported in the literature in individuals affected with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different mutation resulting in the same amino acid change has been classified as pathogenic by our lab (c.3476dupA, p.Tyr1159X). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000580568 SCV001181868 pathogenic Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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