Submissions for variant NM_007294.4(BRCA1):c.2425G>C (p.Glu809Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002459836	SCV002737431	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-15	criteria provided, single submitter	clinical testing	The p.E809Q variant (also known as c.2425G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2425. The glutamic acid at codon 809 is replaced by glutamine, an amino acid with highly similar properties. A different alteration at this position, p.E809G, was reported in one individual with breast cancer diagnosed at age 39 (Darooei M et al. Tumour Biol. 2017 Feb;39:1010428317694303). This amino acid position is not well conserved in available vertebrate species. In addition, p.E809Q is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. 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	RCV002459836	SCV003847674	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005098130	SCV005731845	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 809 of the BRCA1 protein (p.Glu809Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1791084). 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 BRCA1 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.