ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1571G>C (p.Arg524Pro) (rs63751207)

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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) RCV000076197 SCV000107214 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Abrogated function & 2 MSI-H tumours
Ambry Genetics RCV000165648 SCV000216385 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-12 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting pathogenic classification
University of Washington Department of Laboratory Medicine, University of Washington RCV000076197 SCV000266080 likely pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000256140 SCV000322357 likely pathogenic not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1571G>C at the cDNA level, p.Arg524Pro (R524P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant was observed in at least one individual with a history suspicious for Muir-Torre syndrome. While tumor tissue from this individual was shown to have microsatellite instability (MSI-H), mismatch repair proteins were present on immunohistochemical (IHC) staining (Mangold 2004). Although functional studies were inconsistent with regards to this variant's effect on the interaction with MSH6 protein, MSH2 Arg524Pro was consistently associated with defective mismatch repair (MMR) both in vitro and in cells, abolishment of the dominant mutator phenotype, deficient ATPase activity, reduced mismatch-binding in vitro and MNNG-induced chromatin-binding in cells, and decreased MMR protein complex assembly (Boyer 1995, Guerrette 1998, Clark 1999, Drotschmann 1999, Heinen 2002, Mastrocola 2010). MSH2 Arg524Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg524Pro occurs at a position that is conserved across species, and is located within the clamp domain which interacts with MSH6 and MSH3, and stabilizes interaction with EXO1 (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Arg524Pro to be a likely pathogenic variant.
Invitae RCV000531855 SCV000625286 pathogenic Hereditary nonpolyposis colon cancer 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 524 of the MSH2 protein (p.Arg524Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (rs63751207, ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome cancers (PMID: 7937795, 15849733, 18931482, 26845104), and an individual affected with Muir-Torre syndrome (PMID: 15235030). It has also been shown to segregate with Lynch syndrome cancers in two different families (Invitae). ClinVar contains an entry for this variant (Variation ID: 1759). Experimental studies in yeast and human cell lines have shown that this missense change affects mismatch repair (MMR) protein complex formation and impairs the MMR function of the MSH2 protein (PMID: 10469597, 7937795, 17594722, 206672385). For these reasons, this variant has been classified as Pathogenic.
Color RCV000165648 SCV000684947 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000076197 SCV000700092 likely pathogenic Lynch syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256140 SCV000889416 likely pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076197 SCV000919690 likely pathogenic Lynch syndrome 2018-02-02 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1571G>C (p.Arg524Pro) results in a non-conservative amino acid change located in the DNA mismatch repair clamp and core domains 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 277144 control chromosomes. The c.1571G>C variant has been reported in the literature in at least one individual affected with Lynch Syndrome and/or Muir-Torre syndrome(Mangold_2004, Mangold_2005). These data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating the impact on protein function, including mismatch repair deficiency, mismatch DNA strand binding, and MMR complex formation. The most pronounced variant effect results in <10% of normal activity (Drotschmann_1999, Heinen_2002, Gammie_2007). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with each classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000001829 SCV000021985 pathogenic Lynch syndrome I 1994-09-27 no assertion criteria provided literature only

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