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

dbSNP: rs746306598

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002536057	SCV002966439	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-24	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 667010). For these reasons, this variant has been classified as Pathogenic.
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.