Submissions for variant NM_007294.4(BRCA1):c.2083G>A (p.Asp695Asn)

dbSNP: rs28897681

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130220	SCV000185059	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	The p.D695N variant (also known as c.2083G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2083. The aspartic acid at codon 695 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported in one hereditary breast ovarian cancer family from South Africa, however it segregated with disease in only two of three affected sisters and ethnically matched controls were not available (Greenman J et al. Genes Chromosomes Cancer. 1998 Mar;21(3):244-9). In an additional study, this alteration was reported as neutral based on several functional assays assessing the effect of p.D695N on BRCA1-selectable conditional knockout mouse embryonic stem cells (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55). 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.
Counsyl	RCV000111765	SCV000487950	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000985379	SCV000520968	likely benign	not provided	2020-01-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23867111, 9523200, 26689913, 15385441)
Color Diagnostics, LLC DBA Color Health	RCV000130220	SCV000906721	benign	Hereditary cancer-predisposing syndrome	2016-11-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985379	SCV001133512	likely benign	not provided	2023-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440541	SCV001362867	likely benign	not specified	2024-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2083G>A (p.Asp695Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2083G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Greenman 1998) and colorectal carcinoma (Wei_2016). Greenman_1998 reports a family of three affected sisters, which one of the affected sisters did not carry the variant of interest, therefore, suggesting lack of cosegregation with disease. Two functional studies found the variant to not affect HDR activity (Lu_2015) and can rescue proliferation (Bouwman_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23867111, 9523200, 26689913, 27300552, 31867841). ClinVar contains an entry for this variant (Variation ID: 54455). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001324951	SCV001515922	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 695 of the BRCA1 protein (p.Asp695Asn). This variant is present in population databases (rs28897681, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9523200, 31907386). ClinVar contains an entry for this variant (Variation ID: 54455). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23867111, 26689913, 32546644). 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.
Sema4, Sema4	RCV000130220	SCV002538089	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130220	SCV003849515	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).
PreventionGenetics, part of Exact Sciences	RCV004554655	SCV004119852	uncertain significance	BRCA1-related disorder	2022-11-11	criteria provided, single submitter	clinical testing	The BRCA1 c.2083G>A variant is predicted to result in the amino acid substitution p.Asp695Asn. This variant was reported in individuals with breast cancer/ovarian cancer (reported as D695N in Table 1, Greenman et al 1998. PubMed ID: 9523200; Table1, Bouwman et al 2013. PubMed ID: 23867111; Supplementary Data File S1, Kim et al 2020. PubMed ID: 31907386; Table S1, Dong et al 2020. PubMed ID: 32467295). Functional studies suggested that p.Asp695Asn variant does not affect normal HDR activity (Table S22, Lu et al. 2015. PubMed ID: 26689913; Table S2, Bouwman et al 2020. PubMed ID: 32546644). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41245465-C-T). In ClinVar, this variant is interpreted as benign/likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/54455/?new_evidence=false). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111765	SCV000144295	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-06	no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677807	SCV000803966	uncertain significance	Breast neoplasm	2017-09-05	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000985379	SCV001742693	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000985379	SCV001906043	likely benign	not provided		no assertion criteria provided	clinical testing