Submissions for variant NM_000179.3(MSH6):c.1969C>T (p.Gln657Ter)

dbSNP: rs1114167709

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491722	SCV000580149	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.Q657* pathogenic mutation (also known as c.1969C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1969. This changes the amino acid from a glutamine 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.
GeneDx	RCV000494682	SCV000582359	pathogenic	not provided	2015-08-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 c.1969C>T at the cDNA level and p.Gln657Ter (Q657X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000494682	SCV001134403	pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204100	SCV001375291	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-01-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 428316). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln657*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293606	SCV001482223	likely pathogenic	Hereditary nonpolyposis colon cancer	2021-02-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1969C>T (p.Gln657X) 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. The variant was absent in 251144 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1969C>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003449296	SCV004185611	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.
All of Us Research Program, National Institutes of Health	RCV004003454	SCV004838192	pathogenic	Lynch syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual affected with endometrial cancer (PMID: 29345684). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.