Submissions for variant NM_000251.3(MSH2):c.2168C>T (p.Ser723Phe)

dbSNP: rs63750794

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802176	SCV000941994	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-28	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 11920458, 33193653). ClinVar contains an entry for this variant (Variation ID: 90913). 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. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 22102614, 26951660, 31237724, 33357406). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465506	SCV002760647	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003320558	SCV004186615	likely pathogenic	Lynch syndrome 1	2023-08-07	criteria provided, single submitter	clinical testing	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].
Color Diagnostics, LLC DBA Color Health	RCV003584545	SCV004356726	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV003584545	SCV005033608	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-14	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV002465506	SCV005202073	likely pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	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)
Cancer Genome Medicine, Jichi Medical University	RCV003320558	SCV004024552	pathogenic	Lynch syndrome 1	2022-07-13	no assertion criteria provided	clinical testing	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.