ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2974G>T (p.Glu992Ter)

dbSNP: rs774755404
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001381422 SCV001579805 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-27 criteria provided, single submitter clinical testing Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu992*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics RCV002438887 SCV002749205 pathogenic Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing The p.E992* pathogenic mutation (also known as c.2974G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 2974. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017826 SCV004847760 likely pathogenic Lynch syndrome 2019-05-08 criteria provided, single submitter clinical testing The p.Glu992X variant in MSH6 has not been previously reported in individuals with Lynch Syndrome and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 992, 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 summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2.

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