Submissions for variant NM_000059.4(BRCA2):c.1273G>A (p.Glu425Lys)

dbSNP: rs786203512

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166847	SCV000217661	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	clinical testing	The p.E425K variant (also known as c.1273G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1273. The glutamic acid at codon 425 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705017	SCV000833995	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-04	criteria provided, single submitter	clinical testing	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. 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. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 425 of the BRCA2 protein (p.Glu425Lys). 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: 187152).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166847	SCV003849954	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).
Color Diagnostics, LLC DBA Color Health	RCV000166847	SCV004361220	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 425 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported once in a family suspected to be affected with hereditary breast and ovarian cancer (Leiden Open Variation Database BRCA2_003664). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.