ClinVar Genomic variation as it relates to human health

The MSH2 c.2164G>T; p.Val722Phe variant (rs587781996), to our knowledge, is not reported in the medical literature, but is reported in the ClinVar database (Variation ID: 408474). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 722 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. A different variant at this codon (p.Val722Ile) is reported in the literature in an individual with Lynch syndrome (Lagerstedt-Robinson 2016), and in an individual with breast/ovarian cancer but this individual also carried a pathogenic frameshift BRCA2 variant (Dominguez-Valentin 2018). Due to limited information, the clinical significance of the p.Val722Phe variant is uncertain at this time. REFERENCES Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835.

Variant summary: MSH2 c.2164G>T (p.Val722Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2164G>T has been reported in the literature in at least one individual affected with early onset colorectal cancer (CRC) (Thutkawkorapin_2019). This report however, does 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 722 of the MSH2 protein (p.Val722Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30809968). ClinVar contains an entry for this variant (Variation ID: 408474). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.V722F variant (also known as c.2164G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2164. The valine at codon 722 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in a cohort of early-onset colorectal cancer patients undergoing whole exome sequencing (Thutkawkorapin J et al. Mol Genet Genomic Med, 2019 05;7:e605). 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 neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.