Submissions for variant NM_000059.4(BRCA2):c.5126A>C (p.Asp1709Ala)

dbSNP: rs786202836

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165854	SCV000216603	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.D1709A variant (also known as c.5126A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5126. The aspartic acid at codon 1709 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). 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.
GeneDx	RCV000236825	SCV000293349	uncertain significance	not provided	2024-03-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal or family history of breast, ovarian and/or prostate cancer (PMID: 32438681, 35402282, 35534704, 37842866); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5354A>C; This variant is associated with the following publications: (PMID: 32438681, 35944511, 35402282, 32377563, 29884841, 31853058, 37842866, 35534704)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637498	SCV000758959	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165854	SCV000903161	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 1709 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 three individuals affected with breast or ovarian cancer (PMID: 32438681, 35402282) and in one unaffected individual (PMID: 35944511). This variant has been identified in 1/226644 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.
Sema4, Sema4	RCV000165854	SCV002533926	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000236825	SCV003830150	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165854	SCV003847014	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236825	SCV004219670	uncertain significance	not provided	2024-03-21	criteria provided, single submitter	clinical testing	The BRCA2 c.5126A>C (p.Asp1709Ala) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35402282 (2022), 32438681 (2020)). Additionally, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000044 (1/226644 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.
All of Us Research Program, National Institutes of Health	RCV003995460	SCV004845772	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 1709 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 an individual affected with ovarian cancer (PMID: 32438681). This variant has been identified in 1/226644 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.
Fulgent Genetics, Fulgent Genetics	RCV005008080	SCV005633928	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-04-05	criteria provided, single submitter	clinical testing