ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2021G>A (p.Gly674Asp) (rs267607996)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076363 SCV000107390 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
GeneDx RCV000254985 SCV000322163 likely pathogenic not provided 2015-09-10 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2021G>A at the cDNA level, p.Gly674Asp (G674D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant was observed in at least four individuals with a personal history of one or more Lynch Syndrome-associated cancers and was reported to co-segregate with cancer in one family (Raedle 2001, Brieger 2011, Parc 2003). The corresponding variant in yeast, G693D, has been studied in numerous assays, and although it does not appear to impact Msh2p-Msh6p binding (Alani 1997, Gammie 2007), it has exhibited features supportive of pathogenicity including a dominant negative, high mutator phenotype (Studamire 1999, Gammie 2007), a reduction of protein expression (Gammie 2007), and at least a partial defect in ATP binding and ATPase activity (Kijas 2003, Bowers 2000). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). MSH2 Gly674Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly674Asp occurs at a position that is conserved across species and is located in the ATPase domain, ATP-binding motif and region of interaction with EXO1 (Lutzen 2008, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider MSH2 Gly674Asp to be a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000076363 SCV000917714 pathogenic Lynch syndrome 2018-07-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2021G>A (p.Gly674Asp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246190 control chromosomes. c.2021G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome, including cosegregation with disease in one family (Parc_2003). In addition, several other variants at the same codon (p.G674A, p.G674R, and p.G674S) are reported as being associated with colorectal cancer, suggesting it is important for protein function. These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. Although protein:protein interactions such as MSH2-MSH6 binding were not affected by the variant (Gammie_2007), MMR function was found to be defective and ATP-mediated dissocation in the presence of mismatch DNA was also impaired (Gammie_2007; Kijas_2003). Overall, the most pronounced variant effect in these functional studies results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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