Submissions for variant NM_000059.4(BRCA2):c.7456A>G (p.Asn2486Asp)

dbSNP: rs730881556

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160133	SCV000210424	uncertain significance	not provided	2014-10-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7456A>G at the cDNA level, p.Asn2486Asp (N2486D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2486Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2486Asp occurs at a position that is moderately conserved through mammals and is located in the region of interaction with FANCD2 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn2486Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476586	SCV000549514	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 182240). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2486 of the BRCA2 protein (p.Asn2486Asp).
Ambry Genetics	RCV003298190	SCV003995771	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The p.N2486D variant (also known as c.7456A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7456. The asparagine at codon 2486 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.