Submissions for variant NM_000059.4(BRCA2):c.7832A>G (p.Asp2611Gly)

dbSNP: rs80359010

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045327	SCV000073340	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-19	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 2611 of the BRCA2 protein (p.Asp2611Gly). This variant is present in population databases (rs80359010, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 16030099). ClinVar contains an entry for this variant (Variation ID: 52424). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be tolerated (PMID: 19043619). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138, 29394989, 29884841, 33293522). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). 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	RCV000165314	SCV000216036	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.D2611G variant (also known as c.7832A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7832. The aspartic acid at codon 2611 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was identified in 1/110 Hispanic patients with personal or family history of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71). This variant was found to be non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80), while another HDR assay demonstrated p.D2611G to have intermediate functionality, with a probability of pathogenicity of 0.995 and a probability of neutrality of 0.005 (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000113832	SCV000489709	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165314	SCV000683912	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2611 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-mediated DNA repair assays (PMID: 23108138, 29394989), impacts cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 33293522), increases sensitivity to DNA-damaging agents (PMID: 32444794), and was non-functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 16030099). This variant has been identified in 1/251200 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.
GeneDx	RCV001762151	SCV002008888	likely pathogenic	not provided	2024-12-19	criteria provided, single submitter	clinical testing	Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099); Published functional studies demonstrate a damaging effect: impaired homology-directed repair activity, inability to rescue cell lethality in an embryonic stem cell assay, and sensitivity to PARP inhibitors (PMID: 23108138, 29394989, 32377563, 33293522, 32444794, 35665744); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 8060A>G; This variant is associated with the following publications: (PMID: 23108138, 17899372, 19043619, 29884841, 33293522, 31853058, 32042831, 32377563, 29394989, 35665744, 12228710, 27433848, 32444794, 16030099)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001762151	SCV002047165	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000113832	SCV004186060	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV000113832	SCV004845564	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2611 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-mediated DNA repair assays (PMID: 23108138, 29394989), impacts cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 33293522), increases sensitivity to DNA-damaging agents (PMID: 32444794), and was non-functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 16030099). This variant has been identified in 1/251200 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113832	SCV000147201	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045327	SCV001547486	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-04	flagged submission	literature only	Data used in classification The frequency of this variant is 1/123,000 individuals (the GNOMAD population). (PM2-mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (27.1) (PP3-sup). The variant is in the DNA-binding domain of BRCA2 (PM1-sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), which is perfectly validated against genetic epidemiologic data generated by ENIGMA, the variant has a probability of pathogenicity of 1.0 In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.879 and an overall classification of intermediate. (PS3-strong). Data not used in classification There are additional reports of this variant in ClinVar (5), BIC (1) and BRCA2 LOVD (2).