Submissions for variant NM_000059.4(BRCA2):c.5096A>G (p.Asp1699Gly)

gnomAD frequency: 0.00002  dbSNP: rs80358732

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044553	SCV000072566	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1699 of the BRCA2 protein (p.Asp1699Gly). This variant is present in population databases (rs80358732, gnomAD 0.004%). This missense change has been observed in individual(s) with personal and/or family history of breast and ovarian cancer (PMID: 23192404, 27223485, 31780696). ClinVar contains an entry for this variant (Variation ID: 51765). 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 BRCA2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000130603	SCV000185478	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The p.D1699G variant (also known as c.5096A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5096. The aspartic acid at codon 1699 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in Hispanic/Brazilian hereditary breast and/or ovarian cancer cohorts (Rummel S et al. Breast Cancer Res. Treat., 2013 Jan;137:119-25; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Palmero EI et al. Sci Rep, 2018 06;8:9188; Dutil J et al. Sci Rep, 2019 11;9:17769; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Carvalho CM et al. Rev Bras Ginecol Obstet, 2023 Feb;45:74-81). 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.
Eurofins Ntd Llc (ga)	RCV000587656	SCV000225156	uncertain significance	not provided	2015-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000587656	SCV000279807	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast, ovarian, or other cancers (Rummel et al., 2013; Lu et al., 2015; Fernandes et al., 2016; Palmero et al., 2016; Dutil et al., 2019; Guindalini et al., 2022; Matta et al.,, 2022; Villela et al., 2022; Carvalho et al., 2023); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5324A>G; This variant is associated with the following publications: (PMID: 10923033, 19912264, 23192404, 27741520, 27223485, 26689913, 31780696, 34884835, 36329109, 32377563, 29884841, 35264596, 36977404, Villela2022[preprint])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175365	SCV000694828	uncertain significance	not specified	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5096A>G (p.Asp1699Gly) results in a non-conservative amino acid change located in the BRCA2 repeat region (IPR002093) 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 2.2e-05 in 228402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5096A>G has been reported in the literature in individuals affected with breast cancer (example, Rummel_2013, Fernandes_2016, Palmero_2015, Dutil_2019, Urbina-Jara_2021) and in a patient with glioblastoma multiforme (Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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.
Counsyl	RCV000113377	SCV000785237	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587656	SCV000887836	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000022 (5/228402 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 34884835 (2021), 31780696 (2019), 27741520 (2016), 23192404 (2013)), glioblastoma multiforme (PMID: 26689913 (2015)), or a family history of breast/ovarian cancer (PMID: 27223485 (2016)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130603	SCV000911021	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1699 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 been reported in four individuals affected with breast cancer (PMID: 23192404, 27741520, 31780696; Leiden Open Variation Database DB-ID BRCA2_005779), and individuals with a personal or family history of BRCA2-related cancer (PMID: 36329109, 36977404). However, this variant is also located in a BRCA2 region without other clinically significant missense variants (PMID: 31911673). This variant has been identified in 5/228402 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.
Mendelics	RCV000113377	SCV001139102	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044553	SCV002515116	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130603	SCV003846986	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	RCV004803189	SCV004845766	uncertain significance	BRCA2-related cancer predisposition	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1699 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 been reported in four individuals affected with breast cancer (PMID: 23192404, 27741520, 31780696; Leiden Open Variation Database DB-ID BRCA2_005779), and individuals with a personal or family history of BRCA2-related cancer (PMID: 36329109, 36977404). However, this variant is also located in a BRCA2 region without other clinically significant missense variants (PMID: 31911673). This variant has been identified in 5/228402 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000113377	SCV005402410	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-06-23	criteria provided, single submitter	clinical testing	The BRCA2 c.5096A>G (p.Asp1699Gly) missense change has a maximum subpopulation frequency of 0.0070% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool BayesDel predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 23192404, 27223485, 31780696, 36977404). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113377	SCV000146534	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587656	SCV001548584	uncertain significance	not provided		no assertion criteria provided	clinical testing