ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.227_228AG[1] (p.Ser77fs) (rs63749848)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076455 SCV000107478 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Ambry Genetics RCV000220900 SCV000273660 pathogenic Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Invitae RCV000524383 SCV000284145 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-03-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser77Cysfs*4) 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 and families affected with hereditary non-polyposis colorectal cancer (PMID: 9311737, 10874307, 12414824, 15849733, 26552419). This variant is also known as 227-228delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 90953). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076455 SCV000592459 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194000 SCV001363216 pathogenic Hereditary nonpolyposis colon cancer 2019-04-11 criteria provided, single submitter clinical testing Variant summary: MSH2 c.229_230delAG (p.Ser77CysfsX4) 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 (c.387_388delTC, p.Gln130fsX2; c.528_529delTG, p.Cys176X; c.811_814delTCTG, p.Ser271fsX2). The variant was absent in 245728 control chromosomes (gnomAD). The variant, c.229_230delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Wijnen_1997, Otway_2000, Wagner_2002, Mangold_2005, Goodfellow_2015, Rossi_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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