Submissions for variant NM_000179.3(MSH6):c.1993G>T (p.Glu665Ter)

dbSNP: rs1333555322

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602898	SCV000731541	pathogenic	Lynch syndrome	2017-05-24	criteria provided, single submitter	clinical testing	The p.Glu665X variant in MSH6 has not been previously reported in individuals wi th Lynch syndrome or in large population studies. This nonsense variant leads to a premature termination codon at position 665, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is a n established disease mechanism in Lynch syndrome. In summary, this variant meet s criteria to be classified as pathogenic for Lynch syndrome in an autosomal dom inant manner based upon the predicted impact to the protein.
Ambry Genetics	RCV002420653	SCV002720911	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-28	criteria provided, single submitter	clinical testing	The p.E665* pathogenic mutation (also known as c.1993G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1993. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117420	SCV003800676	likely pathogenic	Hereditary nonpolyposis colon cancer	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1993G>T (p.Glu665X) 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. The variant was absent in 251088 control chromosomes. c.1993G>T has been reported in the literature in at least one individual affected with Lynch Syndrome (Zouk_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003411462	SCV004109644	likely pathogenic	MSH6-related condition	2023-05-31	criteria provided, single submitter	clinical testing	The MSH6 c.1993G>T variant is predicted to result in premature protein termination (p.Glu665*). This variant was observed in an individual from a large cohort of predominantly healthy individuals, and was reported as a clinically actionable finding (Table S10, Zouk et al 2019. PubMed ID: 31447099). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/517315/). Nonsense variants in MSH6 are expected to be pathogenic. In summary, this variant is interpreted as likely pathogenic.
Myriad Genetics, Inc.	RCV003451452	SCV004188190	pathogenic	Lynch syndrome 5	2023-08-16	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.