ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1219_1220CT[1] (p.Tyr408fs) (rs587779076)

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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) RCV000076068 SCV000107081 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing a premature termination codon
Ambry Genetics RCV000491679 SCV000580435 pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000076068 SCV000696200 pathogenic Lynch syndrome 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1221_1222delCT (p.Tyr408Serfs) 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.1576delA, p.Thr526fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121304 control chromosomes. Multiple reputable databases classified this variant as pathogenic including InSIGHT and UMD. In addition, this variant is located in the DNA mismatch repair protein MutS, core domain (InterPro). The variant of interest has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as pathogenic.
Invitae RCV001049389 SCV001213435 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr408Serfs*8) 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 reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 90572). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.

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