ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2983G>T (p.Glu995Ter) (rs63750258)

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Total submissions: 4
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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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America 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 colon cancer 2019-12-03 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.

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