ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8542G>C (p.Glu2848Gln)

dbSNP: rs587781893
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130229 SCV000185069 likely benign Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000768608 SCV000324854 uncertain significance Breast and/or ovarian cancer 2015-12-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000257963 SCV000758974 uncertain significance Hereditary breast ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing 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. This sequence change replaces glutamic acid with glutamine at codon 2848 of the BRCA2 protein (p.Glu2848Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141633). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477542 SCV004220614 uncertain significance not provided 2023-09-14 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual undergoing multigene panel testing (PMID: 31853058 (2020)) and was called a variant of unknown significance based on multifactorial likelihood analysis (PMIDs: 31853058 (2020) and 35665744 (2022)). In a cell-based homology directed DNA repair activity assay this variant showed a neutral effect, however additional studies are needed to determine the global effect of this variant on BRCA2 protein function (PMID: 29884841 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.

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