Submissions for variant NM_000059.4(BRCA2):c.6014A>G (p.Asp2005Gly)

dbSNP: rs876658259

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214421	SCV000273269	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-04	criteria provided, single submitter	clinical testing	The p.D2005G variant (also known as c.6014A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6014. The aspartic acid at codon 2005 is replaced by glycine, an amino acid with similar properties. In a study of 1854 high-risk BR/OV cancer kindreds in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691490	SCV000819273	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2005 of the BRCA2 protein (p.Asp2005Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 229901). 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	RCV000214421	SCV003850857	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).
All of Us Research Program, National Institutes of Health	RCV004804862	SCV005424513	uncertain significance	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2005 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and/or ovarian cancer (PMID: 25415331, 27062684) and in an individual referred for hereditary cancer genetic testing (PMID: 31853058). In addition, a multifactorial likelihood analysis suggested that this variant may be pathogenic (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.