Submissions for variant NM_007294.4(BRCA1):c.2263G>A (p.Glu755Lys)

gnomAD frequency: 0.00002  dbSNP: rs41286296

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216413	SCV000273530	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-09	criteria provided, single submitter	clinical testing	The p.E755K variant (also known as c.2263G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2263. The glutamic acid at codon 755 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000483305	SCV000564724	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2263G>A at the cDNA level, p.Glu755Lys (E755K) 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 2382G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu755Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu755Lys occurs at a position that is not conserved and is located within the DNA-binding domain as well as a region that binds STAT1 (Ouchi 2000, Narod 2004). 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 Glu755Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV001057480	SCV001221977	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229928	SCV002511786	uncertain significance	not specified	2022-04-05	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216413	SCV003847805	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).
All of Us Research Program, National Institutes of Health	RCV003997802	SCV004840708	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 755 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 2/251216 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.