Submissions for variant NM_000059.4(BRCA2):c.5188A>T (p.Asn1730Tyr)

gnomAD frequency: 0.00001  dbSNP: rs397507770

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002336177	SCV002643743	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	The p.N1730Y variant (also known as c.5188A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5188. The asparagine at codon 1730 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was detected in a cohort of 263 men with early-onset prostate cancer (Edwards SM et al. Am J Hum Genet, 2003 Jan;72:1-12). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514198	SCV003442059	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1730 of the BRCA2 protein (p.Asn1730Tyr). This variant is present in population databases (rs397507770, gnomAD 0.002%). This missense change has been observed in individual(s) with prostate cancer (PMID: 12474142). This variant is also known as c.5416A>T. ClinVar contains an entry for this variant (Variation ID: 51809). 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	RCV002336177	SCV003847062	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).
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000576951	SCV000678852	not provided	Familial cancer of breast		no assertion provided	literature only