Submissions for variant NM_007294.4(BRCA1):c.2849C>T (p.Ser950Phe)

dbSNP: rs1555588847

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542549	SCV000635870	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-15	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 462595). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 950 of the BRCA1 protein (p.Ser950Phe).
Color Diagnostics, LLC DBA Color Health	RCV000777275	SCV000912977	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777275	SCV002751793	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	clinical testing	The p.S950F variant (also known as c.2849C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2849. The serine at codon 950 is replaced by phenylalanine, 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000777275	SCV003849305	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	RCV003478149	SCV004219325	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in individuals with BRCA1-related disorders. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.