Submissions for variant NM_007294.4(BRCA1):c.3955G>A (p.Gly1319Ser)

dbSNP: rs431825403

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196014	SCV000254981	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-04	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: 96922). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1319 of the BRCA1 protein (p.Gly1319Ser).
GeneDx	RCV001355094	SCV001996004	uncertain significance	not provided	2019-09-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4074G>A
Ambry Genetics	RCV002371934	SCV002624019	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-26	criteria provided, single submitter	clinical testing	The p.G1319S variant (also known as c.3955G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3955. The glycine at codon 1319 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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	RCV002371934	SCV003847588	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).
Sharing Clinical Reports Project (SCRP)	RCV000083043	SCV000115117	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-06-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355094	SCV001549869	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.G1319S variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs431825403) and ClinVar (classified as uncertain significance by Invitae and Sharing Clinical Reports Project). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.G1319 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.