ClinVar Genomic variation as it relates to human health

Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.987

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 697 of the MSH2 protein (p.Cys697Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer and urothelial carcinoma, as well as an individual undergoing genetic testing for Lynch syndrome (PMID: 28514183, 31111311). ClinVar contains an entry for this variant (Variation ID: 187518). 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. Experimental studies have shown that this missense change affects MSH2 function (PMID: 6951660). 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, 16327991, 17101317, 18951462, 22102614). 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.

This missense variant replaces cysteine with tyrosine 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 a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). In mouse embryonic stem cells, this variant also impacts sensitivity to methylating agents and causes reduced protein expression (PMID: 26951660). This variant has been reported in individuals affected with Lynch syndrome associated cancers (PMID: 31111311; Color internal data), and in an individual undergoing multigene panel testing for hereditary cancer (PMID: 28514183). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position, c.2089T>C (p.Cys697Arg) and c.2090G>T (p.Cys697Phe), are considered to be disease-causing (ClinVar variation ID: 90882, 90883), suggesting that the amino acid at this position is important for protein structure and function. Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.C697Y pathogenic mutation (also known as c.2090G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in an individual diagnosed with pancreatic, kidney and colorectal cancers (Langers AMJ et al. Fam Cancer, 2019 07;18:349-352). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). Another alteration at the same codon, p.C697R (c.2089T>C), 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). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.C697Y is located in a key structural position and is indicated to be even more structurally destabilizing than the other alterations at this same codon (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.