ClinVar Genomic variation as it relates to human health

The p.S723F variant (also known as c.2168C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2168. The serine at codon 723 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with colorectal cancer (Furukawa T et al. Cancer, 2002 Feb;94:911-20; Djursby M et al. Front Genet, 2020 Sep;11:566266). 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 deleterious (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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22102614, 26951660]. This variant is expected to disrupt protein structure [Myriad internal data].

Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 22102614, 26951660, 31237724, 33357406). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 90913). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 11920458, 33193653). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 723 of the MSH2 protein (p.Ser723Phe). 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.

This missense variant replaces serine with phenylalanine at codon 723 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). Functional studies have shown that a cell line with this variant is resistant to DNA damage agent and exhibits microsatellite instability (PMID: 31237724). This variant has been reported in individuals affected with Lynch syndrome (PMID: 11920458, 18566915, 33193653). This variant has not been identified 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; This variant is associated with the following publications: (PMID: 23760103, 11920458, 17720936, 22102614, 26951660, 33357406, 25871441, 18561205, 18822302, 21120944, 18566915, 33193653, 31237724)

This Ser723Phe variant in MSH2 was observed in a Japanese family with Lynch syndrome. Proband and 6 first-degree relatives were suffered related cancers (colorectal, ovarian, uterine). This variant was reported in HNPCC study (PMID: 11920458), and in familial colorectal cancer patients study (PMID:33193653). Experimental studies reported that this variant affected MSH2 function (PMID:17720936, 22102614, 26951660, 21237724, 33357406). In summary, the Ser723Phe variant considered as pathogenic.