Submissions for variant NM_000251.3(MSH2):c.2558A>G (p.Glu853Gly)

dbSNP: rs63750797

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160622	SCV000211220	uncertain significance	not provided	2017-06-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2558A>G at the cDNA level, p.Glu853Gly (E853G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant was observed in one woman with epithelial ovarian cancer and one family with Lynch syndrome-associated cancers (Bonadona 2011, Pal 2012). MSH2 Glu853Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu853Gly occurs at a position that is conserved across species and is located in the ATPase domain (Lutzen 2008). 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 Glu853Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000524394	SCV000548278	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 853 of the MSH2 protein (p.Glu853Gly). This variant is present in population databases (rs63750797, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 21642682, 23047549, 25559809). ClinVar contains an entry for this variant (Variation ID: 91000). 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 not expected to disrupt MSH2 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000583069	SCV000690079	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 853 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). This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and Lynch-syndrome-associated cancer (PMID: 21642682, 25559809). This variant has been identified in 1/251450 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160622	SCV000885714	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing	The MSH2 c.2558A>G; p.Glu853Gly variant (rs63750797) is reported in the literature in individuals with colorectal cancer (Bonadona 2011, Chubb 2015) and an individual with ovarian cancer (Pal 2012). This variant is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 91000). It is found in the general population at a very low allele frequency of 0.0004% (1/246240 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamate at codon 853 is moderately conserved, but computational algorithms (SIFT: Damaging, PolyPhen2: Benign) predict conflicting effects of this variant on the protein. Due to limited information, the clinical significance of the p.Glu853Gly variant is uncertain at this time. REFERENCES Bonadona V et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 Jun 8;305(22):2304-10. Chubb D et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol.2015 Feb 10;33(5):426-32. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90.
Ambry Genetics	RCV000583069	SCV001176851	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	clinical testing	The p.E853G variant (also known as c.2558A>G), located in coding exon 15 of the MSH2 gene, results from an A to G substitution at nucleotide position 2558. The glutamic acid at codon 853 is replaced by glycine, an amino acid with similar properties. This alteration has been reported as a variant of uncertain significance in a family suspected of having Lynch syndrome (Bonadona V et al, JAMA 2011 Jun; 305(22):2304-10) and in a family with early onset familial colorectal cancer (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32). This variant was also reported in 1 of 1893 women with epithelial ovarian cancer (Pal T et al, Br. J. Cancer 2012 Nov; 107(10):1783-90). This alteration has been classified as an uncertain variant by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). 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.
Genetic Services Laboratory, University of Chicago	RCV001818240	SCV002066852	uncertain significance	not specified	2021-02-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2558A>G, in exon 15 that results in an amino acid change, p.Glu853Gly. This sequence change has been described in gnomAD with a low population frequency of 0.00040% (dbSNP rs63750797). The p.Glu853Gly change affects a moderately conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu853Gly substitution. This sequence change has been previously reported in individuals and families with colorectal cancer (PMID: 21642682, 25559809) and ovarian cancer (PMID: 23047549). Due to the lack of sufficient evidences, the clinical significance of the p.Glu853Gly change remains unknown at this time.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492424	SCV004239285	uncertain significance	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997166	SCV004826476	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 853 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). This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and Lynch-syndrome-associated cancer (PMID: 21642682, 25559809). This variant has been identified in 1/251450 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.