Submissions for variant NM_007294.4(BRCA1):c.2833A>G (p.Ser945Gly)

dbSNP: rs1567794085

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759510	SCV000888872	uncertain significance	not provided	2018-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183591	SCV001349382	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869033	SCV002146799	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 945 of the BRCA1 protein (p.Ser945Gly). 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: 619789). 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.
Ambry Genetics	RCV001183591	SCV002748429	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-25	criteria provided, single submitter	clinical testing	The p.S945G variant (also known as c.2833A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2833. The serine at codon 945 is replaced by glycine, 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 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	RCV001183591	SCV003849315	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003229602	SCV003927170	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	a variant of uncertain was detected in the BRCA1 gene (c.2833A>G). This sequence change replaces proline with serine at codon 945 of the BRCA1 protein with glycine (p.Pro1562Arg). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. In-silico predictions show benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 1 pathogenic prediction from M-CAP and the position is not strongly conserved. Therefore, it has been classified as a Variant of Uncertain Significance.