Submissions for variant NM_007294.4(BRCA1):c.2981G>A (p.Cys994Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1238452758

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561966	SCV000668452	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.C994Y variant (also known as c.2981G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2981. The cysteine at codon 994 is replaced by tyrosine, an amino acid with highly dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001326585	SCV001517622	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 994 of the BRCA1 protein (p.Cys994Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 482925). 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 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000561966	SCV001735148	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 994 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 1/250458 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.
GeneDx	RCV001764658	SCV001991112	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Identified in individuals referred for multi-gene panel testing with personal or family history of cancer (PMID: 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 3100G>A; This variant is associated with the following publications: (PMID: 25925381, 32377563, 29884841, 15343273, 31853058)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000561966	SCV003849215	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	RCV004802223	SCV005428543	uncertain significance	BRCA1-related cancer predisposition	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 994 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 1/250458 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.