Submissions for variant NM_000251.3(MSH2):c.2228C>T (p.Ser743Leu)

dbSNP: rs63751155

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507559	SCV000601462	uncertain significance	not specified	2017-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219215	SCV001391141	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 743 of the MSH2 protein (p.Ser743Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with esophageal cancer and/or MSH2-related conditions (PMID: 31396961, 35224146; Invitae). ClinVar contains an entry for this variant (Variation ID: 439191). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002431464	SCV002728875	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-27	criteria provided, single submitter	clinical testing	The p.S743L variant (also known as c.2228C>T), located in coding exon 14 of the MSH2 gene, results from a C to T substitution at nucleotide position 2228. The serine at codon 743 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This variant has been identified as somatic in conjunction with a somatic pathogenic MSH2 variant in a tumor that demonstrated high microsatellite instability with loss of MSH2/MSH6 expression by IHC (Haraldsdottir S et al. Gastroenterology. 2014 Dec;147(6):1308-1316.e1). 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 01;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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV003449448	SCV004186592	likely pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35224146].
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250042	SCV001423967	likely pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing