Submissions for variant NM_000251.3(MSH2):c.596G>A (p.Cys199Tyr)

dbSNP: rs63751136

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160619	SCV000211217	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.596G>A at the cDNA level, p.Cys199Tyr (C199Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant was observed in an individual with a personal and family history consistent with Lynch syndrome (Ewald 2007). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain significance (Thompson 2014). MSH2 Cys199Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Cys199Tyr occurs at a position that is well conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Cys199Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002354269	SCV002658355	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	clinical testing	The p.C199Y variant (also known as c.596G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 596. The cysteine at codon 199 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in an individual whose family history met Amsterdam II criteria for Lynch syndrome and rectal tumor showed loss of MSH2 protein expression on immunohistochemistry (IHC) (Ewald J et al. Br J Surg, 2007 Aug;94:1020-7). Another alteration at the same position, p.C199R, has been classified as pathogenic based on studies demonstrating deficient protein function, segregation with disease, and identification in individuals that met Amsterdam II criteria for Lynch syndrome whose colorectal tumors were MSI-H and displayed loss of MSH2 on IHC (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; Gammie AE et al. Genetics. 2007;177(2):707-21; Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739; Ambry internal data). This variant was not reported in population-based 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. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003452954	SCV004186764	likely pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 33357406].
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089522	SCV005834008	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-18	criteria provided, single submitter	clinical testing	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. 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: 777949, 12386821, 17720936, 18561205, 28422960, 29731845, 30998989, 31237724). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 91147). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 17440950). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 199 of the MSH2 protein (p.Cys199Tyr).