Submissions for variant NM_007294.4(BRCA1):c.3401A>T (p.Glu1134Val)

gnomAD frequency: 0.00001  dbSNP: rs762744684

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220075	SCV000277384	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-17	criteria provided, single submitter	clinical testing	The p.E1134V variant (also known as c.3401A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3401. The glutamic acid at codon 1134 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474129	SCV000549320	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1134 of the BRCA1 protein (p.Glu1134Val). This variant is present in population databases (rs762744684, gnomAD 0.009%). 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: 233080). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV000484803	SCV000564733	uncertain significance	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Identified in individuals referred for multi-gene panel testing with personal or family history of cancer (PMID: 30630528, 31853058); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3520A>T; This variant is associated with the following publications: (PMID: 16616110, 30630528, 29884841, 31911673, 31853058, 32377563)
Counsyl	RCV000663155	SCV000786310	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-06	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000220075	SCV003850457	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484803	SCV004219353	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	The BRCA1 c.3401A>T (p.Glu1134Val) variant has been reported in the published literature in an individual undergoing genetic testing for hereditary cancer (PMID: 31853058 (2020)), and described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000087 (3/34578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000663155	SCV004819960	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1134 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 3/250826 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.