Submissions for variant NM_000059.4(BRCA2):c.2659G>A (p.Glu887Lys)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216162	SCV000273533	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-21	criteria provided, single submitter	clinical testing	The p.E887K variant (also known as c.2659G>A or 2887G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2659. The glutamic acid at codon 887 is replaced by lysine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105,000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species, with Lys as the reference aminoacid in several 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 p.E887K remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796825	SCV000936353	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-09	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. ClinVar contains an entry for this variant (Variation ID: 230105). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 887 of the BRCA2 protein (p.Glu887Lys).
Sema4, Sema4	RCV000216162	SCV002535512	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-22	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216162	SCV003848480	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).

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