Submissions for variant NM_000251.3(MSH2):c.595T>C (p.Cys199Arg)

dbSNP: rs63751110

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076650	SCV000107685	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Invitae	RCV001854333	SCV002269120	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	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 199 of the MSH2 protein (p.Cys199Arg). 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: 9777949, 12386821, 18561205). ClinVar contains an entry for this variant (Variation ID: 91146). 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, 28422960, 29731845, 30998989, 31237724). This variant disrupts the p,Cys199 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17440950). 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315405	SCV004015213	pathogenic	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing	The p.C199R variant (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. Two other alterations at the same amino acid position, p.C199Y and p.C199W, have been reported as likely pathogenic. This variant was not reported in populationbased cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In-silico prediction show pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs no benign predictions. Therefore, this variant has been classified as pathogenic.
Ambry Genetics	RCV004019518	SCV005033626	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-14	criteria provided, single submitter	clinical testing	The p.C199R pathogenic mutation (also known as c.595T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 595. The cysteine at codon 199 is replaced by arginine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in an individual diagnosed with rectal cancer at 28 years of age and a glioblastoma at 37 and whose tumor demonstrated high microsatellite instability and absent staining of MSH2 by immunohistochemistry (IHC). In addition, this individual had a reported family history significant for 2 sisters diagnosed with colorectal cancer, one of which underwent testing and was also found to have the p.C199R alteration (Leung SY et al. Am J Pathol. 1998;153(4):1181-8; Chan TL et al. J. Natl. Cancer Inst., 1999 Jul;91:1221-6). In a separate study, functional assays in yeast demonstrated that the p.C199R (p.C195R in yeast) alteration resulted in a reduction of MSH2 levels to 2% of wild-type, inhibited mismatch repair activity, and destabilized protein subunit interactions. Based on the 3D protein structures provided in this publication, codon 199 (195 in yeast) is crucial for proper interaction between domains 1 and 2 in the inner core (Gammie AE et al. Genetics. 2007;177(2):707-21). Another functional study demonstrated that C199R has reduced nuclear localization compared to the wild type (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). 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 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.