ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2041C>T (p.Gln681Ter) (rs730881762)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491607 SCV000580521 pathogenic Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000520788 SCV000617592 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2041C>T at the cDNA level and p.Gln681Ter (Q681X) at the proteinlevel. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA),and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNAdecay. This variant has been reported at least one family meeting modified Amsterdam criteria for Lynch syndrome(Parc 2003) and is considered pathogenic
Invitae RCV000541933 SCV000625340 pathogenic Hereditary nonpolyposis colon cancer 2018-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln681*) in the MSH2 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 families with hereditary non-polyposis colorectal cancer (PMID: 12624141, 24710284). ClinVar contains an entry for this variant (Variation ID: 428498). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586396 SCV000696227 pathogenic Lynch syndrome 2016-08-12 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2041C>T (p.Gln681X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 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.2113delG, p.Val705fsX5; c.2152C>T, p.Gln718X; c.2633_2634delAG, p.Glu878fsX3). One in silico tool predicts a damaging outcome for this variant. The variant has been reported in affected individuals in the literature and is absent in 121330 control chromosomes. Taken together, this variant is classified as pathogenic.

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