ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1120C>T (p.Gln374Ter) (rs63750558)

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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) RCV000076043 SCV000107056 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing a premature termination codon
Ambry Genetics RCV000162405 SCV000212737 pathogenic Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000076043 SCV000218746 pathogenic Lynch syndrome 2014-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 374 (p.Gln374*). It is expected to result in an absent or disrupted protein product. Truncating sequence changes in MSH2 are known to be pathogenic. This particular truncation has been reported in the literature in a patient affected with Lynch syndrome (PMID: 15849733). For these reasons, this sequence change has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076043 SCV001338280 pathogenic Lynch syndrome 2020-02-07 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1120C>T (p.Gln374X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251398 control chromosomes. c.1120C>T has been reported in the literature in individuals affected with Lynch Syndrome (example, Mangold_2005, Lubomierski_2005, Brieger_2011) and as a germline variant in at-least one individual with a cardiac angiosarcoma who later underwent counseling for Lynch synsrome (Sunami_2019). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing one overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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