ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.24C>G (p.Tyr8Ter)

dbSNP: rs746306598
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825599 SCV000966942 likely pathogenic Lynch syndrome 2018-06-11 criteria provided, single submitter clinical testing The p.Tyr8X variant in MSH6 has not been previously reported in individuals with MSH6-associated cancers or in large population studies. This nonsense variant l eads to a premature termination codon at position 8, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Tyr8X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2.
Ambry Genetics RCV002427080 SCV002742739 likely pathogenic Hereditary cancer-predisposing syndrome 2022-12-21 criteria provided, single submitter clinical testing The p.Y8* variant (also known as c.24C>G), located in coding exon 1 of the MSH6 gene, results from a C to G substitution at nucleotide position 24. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration is identified in an individual whose rectal tumor demonstrated normal mismatch repair protein expression on immunohistochemistry (Ambry internal data). The predicted stop codon occurs in the 5’ end of theMSH6 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV002536057 SCV002966439 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-09-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 667010). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr8*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
Myriad Genetics, Inc. RCV003453747 SCV004187232 pathogenic Lynch syndrome 5 2023-08-09 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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