Submissions for variant NM_000059.4(BRCA2):c.5626G>A (p.Glu1876Lys)

gnomAD frequency: 0.00004  dbSNP: rs397507793

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164837	SCV000215520	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The p.E1876K variant (also known as c.5626G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5626. The glutamic acid at codon 1876 is replaced by lysine, an amino acid with similar properties. This variant has previously been reported in a Nigerian individual diagnosed with breast cancer and in 1 of 396 African American individuals diagnosed with early-onset breast cancer. (Fackenthal JD et al. Int. J. Cancer 2012 Sep; 131(5):1114-23; Pal T et al. Cancer, 2015 Dec;121:4173-80). Of note, this alteration is also designated as c.5854G>A in the published literature. This amino acid position is poorly 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.
GeneDx	RCV000758910	SCV000569915	uncertain significance	not provided	2024-06-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (PMID: 22034289); Also known as 5854G>A; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25256751, 22034289)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637513	SCV000758975	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1876 of the BRCA2 protein (p.Glu1876Lys). This variant is present in population databases (rs397507793, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 22034289, 26287763). ClinVar contains an entry for this variant (Variation ID: 185421). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758910	SCV000887851	uncertain significance	not provided	2024-10-09	criteria provided, single submitter	clinical testing	The BRCA2 c.5626G>A (p.Glu1876Lys) variant has been reported in the published literature in individuals with breast cancer (PMID: 22034289 (2012), 26287763 (2015)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00016 (4/24840 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824652	SCV002074308	uncertain significance	not specified	2022-01-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5626G>A (p.Glu1876Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247820 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5626G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Pal_2015, Fackenthal_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164837	SCV003848965	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000758910	SCV004562654	likely benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995368	SCV004846609	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-15	criteria provided, single submitter	clinical testing