ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2089T>C (p.Cys697Arg)

dbSNP: rs63750961
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076384 SCV000107411 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV002228184 SCV000284136 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 697 of the MSH2 protein (p.Cys697Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 10471663, 10480359, 10612836, 14970868, 17973265, 20937110, 21239990, 21598002). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90882). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 12377806, 17720936). This variant disrupts the p.Cys697 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9298827, 17101317, 18951462, 21239990). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002415564 SCV002727838 pathogenic Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing The p.C697R pathogenic mutation (also known as c.2089T>C), located in coding exon 13 of the MSH2 gene, results from a T to C substitution at nucleotide position 2089. The cysteine at codon 697 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, and has been shows to segregate with disease in multiple large families (Wang Q et al. Hum. Genet.; 1999 105:79-85; Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Brieger A et al. Gut, 2002 Nov;51:677-84; Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7; Yoon SN et al. Int. J. Cancer, 2008 Mar;122:1077-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Pastrello C et al. Genet. Med., 2011 Feb;13:115-24). A functional study using a cDNA-mutant construct showed this alteration has a deleterious effect on mismatch repair function (Brieger A et al. Gut, 2002 Nov;51:677-84). An additional functional analysis using the yeast homolog, msh2-C716R, has shown this alteration results in only 5% relative yeast Msh2 expression (Gammie AE et al. Genetics, 2007 Oct;177:707-21). This alteration has been classified as 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. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.C697R is classified as a pathogenic mutation.
PreventionGenetics, part of Exact Sciences RCV004537293 SCV004119248 pathogenic MSH2-related disorder 2023-03-30 criteria provided, single submitter clinical testing The MSH2 c.2089T>C variant is predicted to result in the amino acid substitution p.Cys697Arg. This variant has been reported in individuals with Lynch syndrome (Table 1, Wang et al. 1999. PubMed ID: 10480359; Table 1, Ponz de Leon et al. 2004. PubMed ID: 14970868; Table 1, Yoon et al. 2008. PubMed ID: 17973265; Table 2, Thodi et al. 2010. PubMed ID: 20937110; Table 3, Pastrello et al. 2011. PubMed ID: 21239990). The results of in vitro and in vivo experimental studies suggest this variant impacts protein function (Figures 2, 4, and 6, Brieger et al. 2002. PubMed ID: 12377806; Table 2, Gammie et al. 2007. PubMed ID: 17720936; Table S1, Bouvet et al. 2019. PubMed ID: 30998989; Table 2, Rath et al. 2019. PubMed ID: 31237724). This variant is predicted to be pathogenic by mismatch repair (MMR) gene and other in silico tools (Table 4, Pastrello et al. 2011. PubMed ID: 21239990; Table 3, Ali et al. 2012. PubMed ID: 22290698; Table 2, Thompson et al. 2013. PubMed ID: 22949387). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating that it is rare. It is interpreted as pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/90882). An alternate nucleotide change affecting the same amino acid (p.Cys697Phe) has been associated with Lynch syndrome and interpreted as pathogenic in ClinVar (Table 1, Wehner et al. 1997. PubMed ID: 9298827; Table 1, Ollila et al. 2006. PubMed ID: 17101317; Table 1, Ollila et al. 2008. PubMed ID: 18951462; https://preview.ncbi.nlm.nih.gov/clinvar/variation/90883/). The c.2089T>C (p.Cys697Arg) variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health RCV000076384 SCV004822611 pathogenic Lynch syndrome 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces cysteine with arginine at codon 697 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant impacts MSH2 function in 6-thioguanine sensitivity assays (PMID: 26951660, 33357406). This variant has been reported in individuals and families affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 10480359, 10612836, 14970868, 17973265, 20937110, 21239990, 21598002). It has been described that this variant segregates with disease (PMID: 10612836). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.2090G>T (p.Cys697Phe), c.2090G>A (p.Cys697Tyr), c.2090G>C (p.Cys697Ser), and c.2091T>G (p.Cys697Trp) are considered to be disease-causing (ClinVar variation ID: 90883, 187518, 856441, 2453475), suggesting that this position is important for the protein function. Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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