Submissions for variant NM_007294.4(BRCA1):c.4679G>T (p.Gly1560Val)

gnomAD frequency: 0.00001  dbSNP: rs564757581

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131946	SCV000187003	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-26	criteria provided, single submitter	clinical testing	The p.G1560V variant (also known as c.4679G>T), located in coding exon 14 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4679. The glycine at codon 1560 is replaced by valine, an amino acid with dissimilar 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.
Invitae	RCV000461613	SCV000549398	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1560 of the BRCA1 protein (p.Gly1560Val). This variant is present in population databases (rs564757581, 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: 142627). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759542	SCV000888921	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250292 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a single study of individuals with hereditary breast and/or ovarian cancer (PMID: 29168416 (2018)). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000759542	SCV002577055	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4798G>T; This variant is associated with the following publications: (PMID: 11301010, 10220405, 29168416)
PreventionGenetics, part of Exact Sciences	RCV003415965	SCV004116965	uncertain significance	BRCA1-related condition	2023-02-22	criteria provided, single submitter	clinical testing	The BRCA1 c.4679G>T variant is predicted to result in the amino acid substitution p.Gly1560Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41223252-C-A) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142627/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.