Submissions for variant NM_000251.3(MSH2):c.997T>C (p.Cys333Arg)

dbSNP: rs63750468

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000076777	SCV000259666	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 333 of the MSH2 protein (p.Cys333Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11379475; Invitae). ClinVar contains an entry for this variant (Variation ID: 91272). 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%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 20176959). This variant disrupts the p.Cys333 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16175654, 17101317, 18951462, 21642682, 26951660). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491354	SCV000580566	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-20	criteria provided, single submitter	clinical testing	The p.C333R pathogenic mutation (also known as c.997T>C), located in coding exon 6 of the MSH2 gene, results from a T to C substitution at nucleotide position 997. The cysteine at codon 333 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation was detected in an individual with early-onset colorectal cancer who met Amsterdam criteria and whose tumor revealed loss of MSH2 and MSH6 protein expression on IHC (Ambry internal data). This alteration was also reported in an individual with colorectal cancer diagnosed at the age of 62; his colorectal tumor showed high microsatellite instability (MSI-H) (Adebamowo CA et al. Afr J Med Med Sci. 2000 Mar; 29(1):71-3). Based on internal structural analysis, the p.C333R alteration results in strong perturbation of the region and is significantly more destabilizing than known pathogenic variants in the region (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92; Obmolova G et al. Nature. 2000 Oct; 407(6805):703-10). 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). Functional studies in yeast using recombinant protein expressing the homologous residue, p.C345R, demonstrated loss of yeast MSH6 subunit interaction, reduced mismatch repair activity, and reduced protein expression compared to wild type (Gammie AE et al. Genetics. 2007 Oct;177(2):707-21; Martinez SL et al. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV002280101	SCV002568681	pathogenic	not provided	2022-06-14	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; Observed in patients with a personal history of a Lynch syndrome associated cancer, with one patient showing tumor studies consistent with pathogenic variants in this gene (Adebamowo 2000, Roth 2016); Published functional studies demonstrate a damaging effect: mutator phenotype comparable to MSH2 null allele, loss of Msh3 and Msh6 subunit interaction, and decreased protein expression (Gammie 2007, Martinez 2010, Arlow 2013); This variant is associated with the following publications: (PMID: 11379475, 23248292, 17720936, 20176959, 16995940, 26333163, 11048710, 18383312, 27357288, 30212499, 33357406, 31118792, 18822302, 21120944)
Myriad Genetics, Inc.	RCV003452982	SCV004188054	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].