Submissions for variant NM_000251.3(MSH2):c.2621A>G (p.Tyr874Cys)

gnomAD frequency: 0.00002  dbSNP: rs775390721

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630014	SCV000750970	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776212	SCV000911370	likely benign	Hereditary cancer-predisposing syndrome	2015-09-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781567	SCV000919719	uncertain significance	not specified	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2621A>G (p.Tyr874Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246210 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2621A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000776212	SCV002740793	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	The p.Y874C variant (also known as c.2621A>G), located in coding exon 15 of the MSH2 gene, results from an A to G substitution at nucleotide position 2621. The tyrosine at codon 874 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478344	SCV004220988	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (5/30610 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV003478344	SCV005411708	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	PM2
PreventionGenetics, part of Exact Sciences	RCV004533306	SCV004715133	uncertain significance	MSH2-related disorder	2023-12-03	no assertion criteria provided	clinical testing	The MSH2 c.2621A>G variant is predicted to result in the amino acid substitution p.Tyr874Cys. This variant has been reported in an individual with breast cancer (Table S6, Akcay et al. 2021. PubMed ID: 32658311). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant has conflicting interpretations of benign, likely benign. and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/525750/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.