Submissions for variant NM_000059.4(BRCA2):c.4547T>A (p.Ile1516Asn)

dbSNP: rs80358689

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317093	SCV001507740	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-12-01	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs80358689, ExAC 0.002%). This sequence change replaces isoleucine with asparagine at codon 1516 of the BRCA2 protein (p.Ile1516Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51668). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics	RCV002336169	SCV002639933	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	clinical testing	The p.I1516N variant (also known as c.4547T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 4547. The isoleucine at codon 1516 is replaced by asparagine, an amino acid with dissimilar properties. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002336169	SCV003850598	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113318	SCV000146444	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-03-30	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735550	SCV000863688	uncertain significance	Breast and/or ovarian cancer	2001-03-02	no assertion criteria provided	clinical testing