Submissions for variant NM_007294.4(BRCA1):c.788G>A (p.Gly263Asp)

gnomAD frequency: 0.00001  dbSNP: rs397509319

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159945	SCV000210088	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 907G>A; This variant is associated with the following publications: (PMID: 20215511, 9582019, 9926942, 9788437, 15343273)
Ambry Genetics	RCV000165328	SCV000216051	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.G263D variant (also known as c.788G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 788. The glycine at codon 263 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000409328	SCV000488381	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-03-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559360	SCV000636077	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 263 of the BRCA1 protein (p.Gly263Asp). 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: 182127). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165328	SCV001342717	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 263 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582635	SCV001821340	uncertain significance	not specified	2021-08-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.788G>A (p.Gly263Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.788G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159945	SCV002046621	uncertain significance	not provided	2021-01-29	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165328	SCV003847941	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).
All of Us Research Program, National Institutes of Health	RCV000409328	SCV004818410	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 263 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.