ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2558A>G (p.Glu853Gly) (rs63750797)

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Total submissions: 5
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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 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 853 of the MSH2 protein (p.Glu853Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (rs63750797, ExAC no frequency). This variant has been observed in individuals and families with colorectal cancer (PMID: 21642682, 25559809) and ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 91000). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000583069 SCV000690079 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
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 2019-08-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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