Submissions for variant NM_000059.4(BRCA2):c.8134G>A (p.Asp2712Asn)

gnomAD frequency: 0.00003  dbSNP: rs80359056

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045427	SCV000073440	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-31	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 2712 of the BRCA2 protein (p.Asp2712Asn). This variant is present in population databases (rs80359056, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 52509). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). 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	RCV000130697	SCV000185584	likely benign	Hereditary cancer-predisposing syndrome	2020-08-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000218294	SCV000279256	uncertain significance	not provided	2019-05-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20104584, 26494726, 19043619, 26343386, 29884841)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083144	SCV000743342	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000083144	SCV000744533	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000083144	SCV000786077	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130697	SCV002531914	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218294	SCV004220589	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251328 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 (PMID: 20104584 (2010)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). One functional analysis utilizing a homology-directed repair (HDR) assay suggested that this variant does not affect protein function (PMID: 29884841 (2019)), but additional studies are needed to conclusively determine the effect of this variant on gene or gene product. 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	RCV000130697	SCV004362733	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2712 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). Functional studies have shown that this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 35736817). This variant has been reported in an individual affected with breast cancer (PMID: 20104584). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991;Leiden Open Variation Database DB-ID BRCA2_000283). This variant has been identified in 1/251328 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	RCV003993777	SCV004813673	uncertain significance	not specified	2024-02-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8134G>A (p.Asp2712Asn) results in a conservative amino acid change in 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 4e-06 in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8134G>A has been reported in the literature in individual(s) affected with contralateral breast cancer, without strong evidence for causality (example, Borg_2010). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 2/60466 cases, but was also found in 1/53461 controls (Dorling_2021 through LOVD). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 20104584, 19043619, 33471991). ClinVar contains an entry for this variant (Variation ID: 52509). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000083144	SCV004845608	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2712 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). A functional study has shown that this variant does not have a significant effect on homology-directed DNA repair activity (PMID: 29884841). This variant has been reported in individuals affected with breast cancer (PMID: 20104584, 33471991). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=1.768 (95%CI 0.16 to 19.503); p-value=1; Leiden Open Variation Database DB-ID BRCA2_000283) (PMID: 33471991). This variant has been identified in 1/251328 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)	RCV000083144	SCV000115218	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-07-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083144	SCV000147278	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000218294	SCV001906295	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000218294	SCV001958429	likely benign	not provided		no assertion criteria provided	clinical testing