Submissions for variant NM_007294.4(BRCA1):c.2831G>A (p.Cys944Tyr)

dbSNP: rs770769275

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215126	SCV000274480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	The p.C944Y variant (also known as c.2831G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2831. The cysteine at codon 944 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved and tyrosine is a reference amino acid in several 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215126	SCV003849316	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387809	SCV004099900	uncertain significance	not specified	2023-09-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090082	SCV005790175	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-05	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 944 of the BRCA1 protein (p.Cys944Tyr). This variant is present in population databases (rs770769275, gnomAD 0.003%). 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: 230809). 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.