Submissions for variant NM_000059.4(BRCA2):c.4603G>T (p.Ala1535Ser)

dbSNP: rs2072508845

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001962201	SCV002135607	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1535 of the BRCA2 protein (p.Ala1535Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 1366992). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 20684611). 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	RCV003159027	SCV003850650	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).
Ambry Genetics	RCV003159027	SCV004005510	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The p.A1535S variant (also known as c.4603G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4603. The alanine at codon 1535 is replaced by serine, an amino acid with similar properties. This alteration was observed in 1 of 1045 Italian patients with breast and/or ovarian cancer fulfilling established criteria for HBOC genetic testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). 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.
All of Us Research Program, National Institutes of Health	RCV003483846	SCV004831257	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-27	criteria provided, single submitter	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV003483846	SCV004228404	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)