ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2335dup (p.Met779fs) (rs63750149)

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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) RCV000076459 SCV000107488 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Ambry Genetics RCV000490902 SCV000580605 pathogenic Hereditary cancer-predisposing syndrome 2015-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000697514 SCV000826130 pathogenic Hereditary nonpolyposis colon cancer 2018-06-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met779Asnfs*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, referred to as a single base insertion ATG XAATG, has been observed in an individual affected with Lynch syndrome (PMID: 10080150). ClinVar contains an entry for this variant (Variation ID: 90957). 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 RCV000076459 SCV000917710 likely pathogenic Lynch syndrome 2018-04-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2335dupA (p.Met779AsnfsX8) 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 likely pathogenic/pathogenic by our laboratory (eg. c.2460_2462delinsA (p.Val821fsX2), c.2466T>A (p.Cys822X), and c.2633_2634delAG (p.Glu878fsX3)). The variant was absent in 246228 control chromosomes (gnomAD). The variant, c.2335dupA, has been reported in the literature in an individual affected with Lynch Syndrome (Lin_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.

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