ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2629_2630AG[2] (p.Glu878fs) (rs63751618)

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Total submissions: 11
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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 2018-10-01 criteria provided, single submitter clinical testing 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 colorectal neoplasms 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 2020-01-15 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002172 SCV001160032 pathogenic not specified 2018-10-11 criteria provided, single submitter clinical testing The MSH2 c.2633_2634delAG; p.Glu878fs variant, is reported in the literature in multiple individuals and families affected with Lynch syndrome, colorectal cancer, endometrial cancer, or breast cancer (Bapat 1999, Durno 2005, Millar 1999, Miyaki 1995, Rubio 2016, Shin 2004, Sun 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 91015), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, resulting in a premature termination codon in the last exon of the MSH2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Functional analyses of the variant protein have identified a truncated protein product (Bapat 1999), and a mouse model shows phenotypes reminiscent of Lynch syndrome (Wielders 2017). Based on available information, the p.Glu878fs variant is considered to be pathogenic. References Bapat BV et al. Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer. Hum Genet. 1999 Feb;104(2):167-76. Durno C et al. Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. Gut. 2005 Aug;54(8):1146-50. Millar AL et al. Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. Hum Mol Genet. 1999 May;8(5):823-9. Miyaki M et al. Germ line mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. J Mol Med (Berl). 1995 Oct;73(10):515-20. Rubio I et al. Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer. Oncology. 2016;91(3):171-6. Shin YK et al. Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat. 2004 Oct;24(4):351. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Wielders E et al. Truncation of the MSH2 C-terminal 60 amino acids disrupts effective DNA mismatch repair and is causative for Lynch syndrome. Fam Cancer. 2017 Apr;16(2):221-229.
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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