Submissions for variant NM_000059.4(BRCA2):c.4568G>T (p.Gly1523Val)

dbSNP: rs879255451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478902	SCV000567834	uncertain significance	not provided	2015-08-31	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4568G>T at the cDNA level, p.Gly1523Val (G1523V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 4796G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly1523Val 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 Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly1523Val occurs at a position that is not conserved and is located in the RAD51 binding BRC4 motif (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gly1523Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690856	SCV000818585	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1523 of the BRCA2 protein (p.Gly1523Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 252831). 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. 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000239353	SCV002030310	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338791	SCV002636138	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-10	criteria provided, single submitter	clinical testing	The p.G1523V variant (also known as c.4568G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4568. The glycine at codon 1523 is replaced by valine, an amino acid with dissimilar 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002338791	SCV003850620	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).
Sharing Clinical Reports Project (SCRP)	RCV000239353	SCV000297434	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-10-03	no assertion criteria provided	clinical testing