ClinVar Genomic variation as it relates to human health

Variant summary: MSH2 c.2308A>G (p.Ile770Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 1614080 control chromosomes, predominantly at a frequency of 0.00021 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (1.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2308A>G has been reported in the literature in individuals affected with early-onset colorectal cancer and a personal and/or family history of breast cancer (examples, Farrington_1998, Pereira_2022), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.1865C>T , p.Pro622Leu) in an internal specimen, providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not provide details for independent analysis about the variant effect (Qaddoumi_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 18383312, 9718327, 35980532, 26810070). ClinVar contains an entry for this variant (Variation ID: 90955). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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.

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: 27363726].

This variant is associated with the following publications: (PMID: 22290698, 26333163, 22949379, 18383312, 9718327, 27527004, 26810070)

The MSH2 c.2308A>G variant is predicted to result in the amino acid substitution p.Ile770Val. This variant was reported as heterozygous in a single control subject for a colorectal cancer study (Farrington et al. 1998. PubMed ID: 9718327) and was reported as a variant of uncertain significance in a patient with a personal or family history of breast cancer (Table 2, Pereira et al. 2022. PubMed ID: 35980532). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/90955/?new_evidence=true). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Likely benign and reported on 05-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.