Submissions for variant NM_000179.3(MSH6):c.2931C>G (p.Tyr977Ter)

dbSNP: rs63750111

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074788	SCV000107999	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491868	SCV000580278	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.Y977* pathogenic mutation (also known as c.2931C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2931. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This mutation has been reported in two large, unrelated Swedish HNPCC families in which the probands had a personal history of both colon and endometrial cancers. Authors reported this alteration as a Swedish founder mutation (Cederquist K et al. Int. J. Cancer. 2004 Apr;109(3):370-6; Cederquist K et al. Clin. Genet. 2005 Dec;68(6):533-41). This mutation was also observed in a proband with early-onset colorectal cancer and in a patient with endometrial cancer diagnosed at age 53 (DeRycke MS et al. Mol. Genet. Genomic Med. 2017 Sep;5(5):553-569; Tzortzatos G et al. Gynecol. Oncol. 2015 Sep;138(3):717-22). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health	RCV000491868	SCV000905455	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	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, functional studies have not been performed for this variant. This variant has been reported in individuals and families affected with Lynch syndrome and Lynch syndrome-associated cancers (PMID: 14961575, 16283884, 25142776, 25318681, 27601186, 28944238, 31118792) and has been reported to segregate with Lynch syndrome in one family (PMID: 16283884). 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). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV001008655	SCV001168434	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Cederquist 2004, Cederquist 2005, Tzortzatos 2015, Gong 2019); Described as a founder variant in the Swedish population (Cederquist 2005, Therkildsen 2012)
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001008655	SCV001450387	pathogenic	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Invitae	RCV002514330	SCV003524585	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-03	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: 89323). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 14961575, 25142776, 27601186, 28944238). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr977*) 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.	RCV003450952	SCV004188266	pathogenic	Lynch syndrome 5	2023-08-21	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	RCV000074788	SCV004839011	pathogenic	Lynch syndrome	2023-11-07	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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in many individuals affected with Lynch syndrome-related cancers (PMID: 14961575, 16283884, 25142776, 25318681, 27601186, 28944238, 31118792) and has been reported to segregate with Lynch syndrome in one family (PMID: 16283884). 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). Based on the available evidence, this variant is classified as Pathogenic.
GeneReviews	RCV001804805	SCV002054084	not provided	Lynch syndrome 1		no assertion provided	literature only