Submissions for variant NM_000179.3(MSH6):c.2983G>T (p.Glu995Ter)

dbSNP: rs63750258

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074793	SCV000108004	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491673	SCV000580375	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-15	criteria provided, single submitter	clinical testing	The p.E995* pathogenic mutation (also known as c.2983G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 2983. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation has been reported in an individual diagnosed with both breast cancer and colorectal cancer at age 34 as well as in an individual diagnosed with a meningioma at age 51 from a family history meeting Amsterdam and/or revised Bethesda criteria for Lynch syndrome (Vahteristo P et al. Cancer Res., 2001 Aug;61:5718-22; Gylling AH et al. Carcinogenesis, 2008 Jul;29:1351-9). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074793	SCV000695835	likely pathogenic	Lynch syndrome	2017-02-14	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2983G>T (p.Glu995X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. c.3013C>T, p.Arg1005X; c.3052_3053delCT, p.Leu1018fsX4; c.3103C>T, p.Arg1035X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 113186 control chromosomes and has been reported in the literature in two Finnish families with common ancestral origin, both of whom had atypical Lynch Syndrome. In addition, one reputable database has classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV001062414	SCV001227212	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu995*) 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 premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15805151, 22691310, 28874130). ClinVar contains an entry for this variant (Variation ID: 89328). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269505	SCV001449540	pathogenic	not provided	2019-09-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450954	SCV004185696	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.
GeneReviews	RCV001804806	SCV002054082	not provided	Lynch syndrome 1		no assertion provided	literature only