ClinVar Genomic variation as it relates to human health

This missense variant replaces proline with serine at codon 259 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with suspected Lynch syndrome and in individuals with breast cancer (PMID: 21642682, 26976419, 32658311); Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 21642682, 12624141, 26976419, 31391288, 33558524, 32658311, 31422574, 21120944, 18822302, 33357406, 33471991)

Variant summary: MSH2 c.775C>T (p.Pro259Ser) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.775C>T has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome (e.g. Parc_2003, Bonadona_2011, Li_2020, Akcay_2020) and with breast cancer (e.g. Tung_2016, Akcay_2020, Moradian_2021), however, the variant was also found in healthy controls (Dorling_2021) and in cancer-free individuals undergoing whole-exome sequencing as a secondary finding (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The MSH2 c.775C>T variant is predicted to result in the amino acid substitution p.Pro259Ser. This variant has been reported as a variant of uncertain significance in patients with nonpolyposis colorectal cancer (eTable 1, Bonadona et al. 2011. PubMed ID: 21642682). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47639682-C-T). This variant has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/140810/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces proline with serine at codon 259 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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 frequency of this variant in the general population, 0.000004 (1/251078 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 21642682 (2011)), breast cancer (PMID: 26976419 (2016), 33558524 (2021), 32658311 (2021)), and colorectal cancer (PMID: 32658311 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021), 31422574 (2019)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.