Submissions for variant NM_000059.4(BRCA2):c.7795G>A (p.Glu2599Lys)

dbSNP: rs41293509

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223559	SCV000275438	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The p.E2599K variant (also known as c.7795G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7795. The glutamic acid at codon 2599 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the literature in individuals diagnosed with prostate cancer (Kote-Jarai et al. Br J Cancer. 2011 Oct 11;105(8):1230-4) and triple negative breast cancer (Muendlein A et al J Cancer Res Clin Oncol. 2015 Nov;141(11):2005-12). In addition, the variant was detected in conjunction with another pathogenic mutation in the BRCA2 gene in an individual affected with Fanconi Anemia, although phase was not reported (Knies K et al. PLoS One. 2012;7(12):e52648). Furthermore, this alteration was non-functional in a homology directed DNA repair assay (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067846	SCV001232927	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-28	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 2599 of the BRCA2 protein (p.Glu2599Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer or breast cancer and Fanconi anemia (PMID: 21952622, 23285130, 25971625). ClinVar contains an entry for this variant (Variation ID: 231552). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 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.
GeneDx	RCV002225522	SCV002504153	uncertain significance	not provided	2022-04-08	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; Observed with a second BRCA2 variant, phase (cis or trans) not confirmed, in an individual with Fanconi anemia in published literature (Knies 2012); Observed in individuals with a personal history of prostate cancer or breast cancer in published literature (Kote-Jarai 2011, Muendlein 2015); Also known as 8023G>A; This variant is associated with the following publications: (PMID: 21952622, 25971625, 12228710, 23285130)