Submissions for variant NM_002439.5(MSH3):c.2557G>C (p.Glu853Gln)

gnomAD frequency: 0.00004  dbSNP: rs200185323

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812892	SCV000953222	uncertain significance	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 853 of the MSH3 protein (p.Glu853Gln). This variant is present in population databases (rs200185323, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 656464). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001015952	SCV001176847	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The p.E853Q variant (also known as c.2557G>C), located in coding exon 19 of the MSH3 gene, results from a G to C substitution at nucleotide position 2557. The glutamic acid at codon 853 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV001015952	SCV002536066	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268307	SCV002550523	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467463	SCV004196998	uncertain significance	Endometrial carcinoma	2024-03-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000812892	SCV005327426	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV000812892	SCV005411823	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000812892	SCV005623818	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	The MSH3 c.2557G>C (p.Glu853Gln) variant has been reported in the published literature in a cohort of individual with ovarian cancer (PMID: 24448499 (2014)). The frequency of this variant in the general population, 0.00007 (9/128636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV005036192	SCV005666207	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-05-01	criteria provided, single submitter	clinical testing