ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2983G>T (rs63750258)

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Total submissions: 5
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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 2016-08-26 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). 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 2020-10-13 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. This variant is not present in population databases (ExAC no frequency). This variant 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). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269505 SCV001449540 pathogenic not provided 2019-09-18 criteria provided, single submitter clinical testing

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