Submissions for variant NM_007294.4(BRCA1):c.1435G>A (p.Glu479Lys)

dbSNP: rs1064794100

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480844	SCV000567829	uncertain significance	not provided	2015-09-04	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1435G>A at the cDNA level, p.Glu479Lys (E479K) 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 BRCA1 1554G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu479Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu479Lys occurs at a position that is conserved in mammals and is located in the DNA binding domain (Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu479Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001011564	SCV001171900	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The p.E479K variant (also known as c.1435G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1435. The glutamic acid at codon 479 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV002525813	SCV003350709	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-13	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 479 of the BRCA1 protein (p.Glu479Lys). 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: 419779). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001011564	SCV003851302	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).