ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2633_2634delAG (rs63751618)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076517 SCV000107547 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Ambry Genetics RCV000213582 SCV000273598 pathogenic Hereditary cancer-predisposing syndrome 2017-08-16 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)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076517 SCV000592553 pathogenic Lynch syndrome 2012-11-28 criteria provided, single submitter clinical testing
Invitae RCV000548456 SCV000625398 pathogenic Hereditary nonpolyposis colon cancer 2018-12-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH2 gene (p.Glu878Alafs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families with Lynch syndrome or suspected Lynch syndrome (PMID: 8581513, 10196371, 15365995), as well as individuals with endometrial cancer or colorectal cancer (PMID: 27398995, 15845562). ClinVar contains an entry for this variant (Variation ID: 91015). This variant is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Glu878-Thr934) (PMID: 9774676, 18822302, 17531815). An experimental study has shown that this variant does not completely abolish MutSalpha assembly, but impairs the interaction of MSH2 and MSH6 (PMID: 18781619). Therefore, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815), suggesting that deletion of this region of the MSH2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color RCV000213582 SCV000685067 pathogenic Hereditary cancer-predisposing syndrome 2016-09-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076517 SCV000696253 pathogenic Lynch syndrome 2016-11-16 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2633_2634delAG (p.Glu878Alafs) 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.2653C>T (p.Gln885X)). The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories and databases have cited the variant as "Causal/Pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000616983 SCV000744282 pathogenic Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000201958 SCV000778973 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH2 is denoted c.2633_2634delAG at the cDNA level and p.Glu878AlafsX3 (E878AfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAG[delAG]GTTT. The deletion causes a frameshift which changes a Glutamic Acid to an Alanine at codon 878, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. MSH2 c.2633_2634delAG, also published as 2629delAG using alternate nomenclature, has been observed in many families presenting with a Lynch syndrome phenotype (Miyaki 1995, Yuan 1998, Millar 1999, Durno 2005) while tumor testing has consistently shown microsatellite instability (MSI-H) and loss of the MSH2 protein via immunohistochemistry (Konishi 1996, Marcus 1999, Millar 1999, Terdiman 2001, Rubio 2016). Additionally, using mouse embryonic stem cells, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability. We consider this variant to be pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201958 SCV000257181 pathogenic not provided no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000616983 SCV000734204 pathogenic Lynch syndrome I no assertion criteria provided clinical testing

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