ClinVar Genomic variation as it relates to human health

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 26951660, 22949387, 23047549, 29192238, 30833958, 31386297)

The MSH2 c.2203A>G variant is predicted to result in the amino acid substitution p.Ile735Val. This variant has been reported in individuals with ovarian cancer, esophageal cancer, an unspecified cancer type (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table S2, Deng et al. 2019. PubMed ID: 30833958; Table S1, Kiyozumi et al. 2019. PubMed ID: 31386297). In vitro experimental studies suggest that this variant does not result in loss of protein function (Tables S3 and S4, Jia et al. 2020. PubMed ID: 33357406). In silico tools predictions for this variant are conflicting (Table 2, Pal et al. 2012. PubMed ID: 23047549; Table 2, Thompson et al. 2012. PubMed ID: 22949387; Tables S3 and S4, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47703703-A-G; Table S1, Amendola et al. 2015. PubMed ID: 25637381). It has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/161300/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: MSH2 c.2203A>G (p.Ile735Val) results in a conservative amino acid change located in the in the C-terminal domain (IPR000432) and ATP-binding cassette domain (IPR032642) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251638 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2203A>G has been reported in the literature in individuals affected with cancer including colorectal cancer, ovarian cancer, breast cancer, endometrial cancer, prostate cancer and esophageal squamous cell carcinoma (e.g. Pal_2012, Yehia_2018, Deng_2019, Kiyozumi_2019, Tian_2019, Wei_2019, Fujita_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least two publications report experimental evidence suggesting that the variant does not disrupt mismatch repair activity and is a functionally neutral substitution (e.g., Houlleberghs_2016, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 30833958, 33309985, 26951660, 33357406, 31386297, 12376507, 23047549, 30122538, 27974047, 22949387, 31054147, 31248605, 29684080, 31235699). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign, n = 2; likely benign, n = 2; VUS, n = 4). Based on the evidence outlined above, the variant was classified as likely benign.