ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1226_1227del (p.Gln409fs) (rs63750086)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076073 SCV000107088 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing a premature termination codon
GeneDx RCV000212600 SCV000211228 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH2 is denoted c.1226_1227delAG at the cDNA level and p.Gln409ArgfsX7 (Q409RfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TATC[delAG]GGTA. The deletion causes a frameshift, which changes a Glutamine to an Arginine at codon 409, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.1226_1227delAG has been reported in families whose clinical histories are consistent with Lynch syndrome, and in whom tumor testing has demonstrated microsatellite instability (MSI-H) and/or loss of the MSH2/MSH6 proteins via immunohistochemistry (Moslein 1996, Liu 1998, Perez-Carbornero 2011, Egoavil 2013, Goodfellow 2015, Siraj 2015). We consider this variant to be pathogenic.
Ambry Genetics RCV000160629 SCV000212765 pathogenic Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
University of Washington Department of Laboratory Medicine, University of Washington RCV000076073 SCV000266082 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000411649 SCV000489574 pathogenic Lynch syndrome I 2016-10-27 criteria provided, single submitter clinical testing
Invitae RCV000524336 SCV000548145 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln409Argfs*7) 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 affected with Lynch syndrome (PMID: 8872463, 15849733, 19419416, 17569143, 21778331) and individuals affected with endometrial cancer (PMID: 24244552, 26552419, 26845104). ClinVar contains an entry for this variant (Variation ID: 90577). 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 RCV000076073 SCV000592494 pathogenic Lynch syndrome 2014-07-24 criteria provided, single submitter clinical testing
GenePathDx,Causeway Health Care Private Ltd RCV000411649 SCV000616340 pathogenic Lynch syndrome I 2017-08-17 criteria provided, single submitter clinical testing Diagnosed case of FAP
Color RCV000160629 SCV000684917 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000076073 SCV000837829 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212600 SCV000888200 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076073 SCV000917719 pathogenic Lynch syndrome 2018-08-27 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1226_1227delAG (p.Gln409ArgfsX7) 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. The variant was absent in 246188 control chromosomes (gnomAD). The variant, c.1226_1227delAG, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Goodfellow_2015, Mangold_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212600 SCV000691903 pathogenic not provided no assertion criteria provided clinical testing

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