ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1572C>A (p.Tyr524Ter) (rs587779215)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491224 SCV000580145 pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 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 RCV000523866 SCV000618271 pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1572C>A at the cDNA level and p.Tyr524Ter (Y524X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. While this specific variant has not, to our knowledge, been published in the literature, another variant resulting in the same premature stop codon (MSH6 c.1572C>G [p.Tyr524Ter]) has been reported in a women with endometrial cancer (Rubio 2016). Based on currently available evidence, we consider MSH6 Tyr524Ter to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000457937 SCV000695787 pathogenic Lynch syndrome 2016-11-04 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1572C>A (p.Tyr524X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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. c.1784delT/p.Leu595fsX15; c.2230dupG/p.Glu744fsX12; c.2731C>T/p.Arg911X, etc). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121362 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. However, the variant c.1572C>G leading to the same codon change p.Tyr524X in MSH6 is classified as "pathogenic" by InSiGHT, and has been reported in affected individuals. Taken together, according to ACMG guideline, this variant is classified as pathogenic.
Invitae RCV000791425 SCV000551099 pathogenic Hereditary nonpolyposis colon cancer 2018-08-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr524*) 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 not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410426). 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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