Submissions for variant NM_000059.4(BRCA2):c.5632A>G (p.Asn1878Asp)

gnomAD frequency: 0.00003  dbSNP: rs397507358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480280	SCV000570714	uncertain significance	not provided	2016-06-22	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5632A>G at the cDNA level, p.Asn1878Asp (N1878D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). Using alternate nomenclature, this variant would be defined as BRCA2 5860A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1878Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn1878Asp occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). 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 Asn1878Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000581757	SCV000688936	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817294	SCV000957845	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1878 of the BRCA2 protein (p.Asn1878Asp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as c.5860A>G. ClinVar contains an entry for this variant (Variation ID: 421495). 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 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000581757	SCV003848970	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987559	SCV004803534	uncertain significance	not specified	2024-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581757	SCV005028233	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	The p.N1878D variant (also known as c.5632A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5632. The asparagine at codon 1878 is replaced by aspartic acid, an amino acid with highly similar properties. 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.