Submissions for variant NM_000059.4(BRCA2):c.1594G>A (p.Glu532Lys)

dbSNP: rs138734772

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Michigan Medical Genetics Laboratories, University of Michigan	RCV000210974	SCV000195961	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000210974	SCV000786140	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759578	SCV000888985	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000081 (2/247616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae	RCV000804265	SCV000944167	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 188427). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs138734772, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 532 of the BRCA2 protein (p.Glu532Lys). 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.
Ambry Genetics	RCV001012315	SCV001172748	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The p.E532K variant (also known as c.1594G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1594. The glutamic acid at codon 532 is replaced by lysine, an amino acid with similar 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	RCV001012315	SCV003851511	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502252	SCV000591756	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu532Lys was not identified in the literature, nor was it identified in the dbSNP, HGMD, UMD, BIC, and LOVD databases. The variant was reported in the Exome Variant Server ESP Project, with a frequency of 0.0001 in European American alleles; however, this is based on only one occurrence of the variant in that population. Although the p.Glu983 residue is conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. However, this is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.