Submissions for variant NM_000059.4(BRCA2):c.7585G>A (p.Gly2529Ser)

gnomAD frequency: 0.00001  dbSNP: rs398122585

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218797	SCV000275666	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	The p.G2529S variant (also known as c.7585G>A), located in coding exon 14 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7585. The glycine at codon 2529 is replaced by serine, an amino acid with similar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637466	SCV000758926	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-14	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 BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 91483). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs398122585, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2529 of the BRCA2 protein (p.Gly2529Ser).
Color Diagnostics, LLC DBA Color Health	RCV000218797	SCV000911410	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2529 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250996 chromosomes 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	RCV000780001	SCV000916989	uncertain significance	not specified	2018-08-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7585G>A (p.Gly2529Ser) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245744 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.7585G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001550351	SCV001770664	uncertain significance	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); 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 c.7813G>A
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001550351	SCV002046620	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	This variant has not been reported as a germline variant in the published literature. The frequency of this variant in the general population, 0.000004 (1/250996 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003460725	SCV004213606	uncertain significance	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000637466	SCV004228006	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077000	SCV004844430	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2529 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250996 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000077000	SCV000108797	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-13	no assertion criteria provided	clinical testing