Submissions for variant NM_000251.3(MSH2):c.1570C>T (p.Arg524Cys)

gnomAD frequency: 0.00002  dbSNP: rs755818010

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759820	SCV000570933	uncertain significance	not provided	2023-10-04	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 an individual with thyroid cancer (Yehia et al., 2018); Published functional studies demonstrate no damaging effect: mutation rate similar to wild type in yeast model (Ollodart et al., 2021); This variant is associated with the following publications: (PMID: 29684080, 9774676, 18822302, 21120944, 10469597, 15849733, 26845104, 17594722, 31857677, 33357406, 7937795, 18931482, 26951660, 33848333)
Genetic Services Laboratory, University of Chicago	RCV000484414	SCV000595832	uncertain significance	not specified	2016-12-16	criteria provided, single submitter	clinical testing
Invitae	RCV000552575	SCV000625285	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 524 of the MSH2 protein (p.Arg524Cys). This variant is present in population databases (rs755818010, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). However, it has also been observed in multiple individuals without Lynch syndrome related features (Invitae). ClinVar contains an entry for this variant (Variation ID: 421654). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 26951660). This variant disrupts the p.Arg524 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7937795, 10469597, 15849733, 17594722, 18931482, 20672385, 26845104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000569307	SCV000662240	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.R524C variant (also known as c.1570C>T), located in coding exon 10 of the MSH2 gene, results from a C to T substitution at nucleotide position 1570. The arginine at codon 524 is replaced by cysteine, an amino acid with highly dissimilar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 06;218). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759820	SCV000889415	uncertain significance	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484414	SCV002598596	uncertain significance	not specified	2022-09-05	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1570C>T (p.Arg524Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251392 control chromosomes. 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.1570C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004003360	SCV004831713	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 524 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with thyroid cancer (PMID: 29684080). This variant has been identified in 3/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1571G>C (p.Arg524Pro), is considered to be disease-causing (ClinVar variation ID: 1759), suggesting that arginine at this position is important for the protein function. 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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250041	SCV001423966	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing