Submissions for variant NM_007294.4(BRCA1):c.2425G>A (p.Glu809Lys)

gnomAD frequency: 0.00001  dbSNP: rs786204151

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168142	SCV000218802	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 809 of the BRCA1 protein (p.Glu809Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV000569597	SCV000673022	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-06	criteria provided, single submitter	clinical testing	The p.E809K variant (also known as c.2425G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2425. The glutamic acid at codon 809 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.
Counsyl	RCV000662597	SCV000785228	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569597	SCV000904131	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 809 of the BRCA1 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/281900 chromosomes 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985388	SCV001133530	uncertain significance	not provided	2019-03-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000985388	SCV001778679	uncertain significance	not provided	2020-08-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 2544G>A
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569597	SCV003847675	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).