Submissions for variant NM_000059.4(BRCA2):c.4808A>T (p.Asn1603Ile)

dbSNP: rs890665355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563820	SCV000668587	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-08	criteria provided, single submitter	clinical testing	The p.N1603I variant (also known as c.4808A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4808. The asparagine at codon 1603 is replaced by isoleucine, an amino acid with dissimilar properties. In one study, this alteration was detected in 1/146 Caucasians with high-risk breast and/or ovarian cancer family histories (Lu W et al. Fam. Cancer 2012 Sep; 11(3):381-5). 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.
Color Diagnostics, LLC DBA Color Health	RCV000563820	SCV000688897	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000989032	SCV001139096	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283926	SCV001469431	uncertain significance	not provided	2020-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000709312	SCV002274684	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with isoleucine at codon 1603 of the BRCA2 protein (p.Asn1603Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 22476429). ClinVar contains an entry for this variant (Variation ID: 482988). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563820	SCV003852113	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).