Submissions for variant NM_000251.3(MSH2):c.1922G>A (p.Cys641Tyr)

dbSNP: rs786204110

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168044	SCV000218697	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000483193	SCV000570463	uncertain significance	not provided	2016-05-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1922G>A at the cDNA level, p.Cys641Tyr (C641Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Cys641Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Cys641Tyr occurs at a position that is conserved across species and is located in ATPase domain as well as in the region of interaction with EXO1 (Lützen 2008, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Cys641Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563020	SCV000669749	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	The p.C641Y variant (also known as c.1922G>A), located in coding exon 12 of the MSH2 gene, results from a G to A substitution at nucleotide position 1922. The cysteine at codon 641 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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 neutral (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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV000563020	SCV002534426	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150034	SCV003838308	uncertain significance	Breast and/or ovarian cancer	2022-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563020	SCV004356710	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 641 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251456 chromosomes 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.