Submissions for variant NM_000059.4(BRCA2):c.2239G>A (p.Glu747Lys)

dbSNP: rs878853561

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431436	SCV000522175	uncertain significance	not provided	2018-09-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2239G>A at the cDNA level, p.Glu747Lys (E747K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 2467G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Glu747Lys was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu747Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000431436	SCV002046691	uncertain significance	not provided	2021-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861518	SCV002294146	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 747 of the BRCA2 protein (p.Glu747Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 382284). 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.
Ambry Genetics	RCV002429388	SCV002726859	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	The p.E747K variant (also known as c.2239G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2239. The glutamic acid at codon 747 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV002429388	SCV003846595	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).