Submissions for variant NM_000059.4(BRCA2):c.6894A>T (p.Glu2298Asp)

gnomAD frequency: 0.00001  dbSNP: rs876661199

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220725	SCV000279771	uncertain significance	not provided	2016-01-06	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6894A>T at the cDNA level, p.Glu2298Asp (E2298D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 7122A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2298Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu2298Asp occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Glu2298Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000565312	SCV000661435	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The p.E2298D variant (also known as c.6894A>T), located in coding exon 11 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6894. The glutamic acid at codon 2298 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686463	SCV000813982	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2298 of the BRCA2 protein (p.Glu2298Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234753). 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.