ClinVar Genomic variation as it relates to human health

Variant summary: MSH2 c.220A>C (p.Asn74His) results in a conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251978 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.220A>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); Published functional studies suggest no damaging effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (Jia et al., 2020); This variant is associated with the following publications: (PMID: 22949387, 18822302, 21120944, 24728327, 33357406)

The frequency of this variant in the general population, 0.000026 (3/113416 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an unaffected individual of European ethnicity (PMID: 24728327 (2014)). In a large-scale breast cancer association study, the variant was observed in an individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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 missense variant replaces asparagine with histidine at codon 74 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant did not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 3/250616 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces asparagine with histidine at codon 74 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250616 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This alteration is classified as likely 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.

The MSH2 c.220A>C variant is predicted to result in the amino acid substitution p.Asn74His. This variant was reported in 1 case and 0 controls in a study of women with breast cancer (Supplemental Data, Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). It was also reported in one healthy individual in a study of variants in cancer-susceptibility genes in the general population (Bodian et al. 2014. PubMed ID: 24728327). The p.Asn74His substitution was reported as functionally neutral based on an experimental study (Table S5, Jia et al. 2020. PubMed ID: 33357406). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations in ClinVar, ranging from benign to likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/134846/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Uncertain significance and reported on 07-15-2019 by Lab 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.