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 The p.R524P variant (also known as c.1571G>C), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1571. The arginine at codon 524 is replaced by proline, an amino acid with dissimilar properties. This alteration was first reported in a female who was diagnosed at age 38 with MSI-H ovarian cancer with loss of heterozygosity (Orth K et al. Proc. Natl. Acad. Sci. U.S.A. 1994 Sep; 91(20):9495-9). This alteration has also been reported in a patient with the Muir-Torre variant of Lynch syndrome and in a patient meeting Bethesda criteria (Mangold E et al. J. Med. Genet. 2004 Jul; 41(7):567-72; Shirts BH et al. Genet Med. 2016 Oct;18(10):974-81). This alteration is located in the clamp domain and in vitro DNA binding, ATPase and sliding clamp dissociation studies have shown an effect on the mismatch-dependent molecular switch function of the hMSH2-hMSH6 heterodimer (Heinen CD et al. Cancer Cell 2002 Jun; 1(5):469-78). Multiple functional assays have demonstrated that this protein was repair-deficient, unstable, and unable to elicit a DNA checkpoint in response to DNA alkylation damage (Boyer JC et al. Cancer Res. 1995 Dec; 55(24):6063-70; Mastrocola AS et al. Hum. Mutat. 2010 Oct; 31(10):E1699-708; Nielsen SV et al. PLoS Genet. 2017 Apr 19;13(4):e1006739). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species, and the in silico prediction for this alteration is inconclusive. In addition, this alteration was predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 colorectal neoplasms 2020-09-02 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 Health, Inc RCV000165648 SCV000684947 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-31 criteria provided, single submitter clinical testing This missense variant replaces arginine with proline at codon 524 in the MSH3/MSH6 interaction and clamp domain of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant reduces interactions with MSH3 or MSH6 and impairs mismatch repair (MMR) activities (PMID: 8521394, 12124176, 17594722, 20672385). This variant has been reported in individuals with or suspected with Lynch syndrome (PMID: 15849733, 18931482) and in one individual affected with colorectal cancer (PMID: 26845104). This variant has also been reported in one individual with Muir-Torre syndrome (PMID: 15235030). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251063 SCV000919690 likely pathogenic Hereditary nonpolyposis colon cancer 2020-07-29 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 protein MutS, clamp (IPR007861) and DNA mismatch repair protein MutS, core (IPR007696) 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 251380 control chromosomes. c.1571G>C has been reported in the literature in individuals affected with Muir-Torre syndrome (e.g. Mangold_2004), ovarian cancer (e.g. Orth_1994), and colon cancer (e.g. Shirts_2016). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Drotschmann_1999, Heinen_2002, Gammie_2007, Mastrocola_2010). The most pronounced variant effect results in <10% of normal activity. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/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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