Submissions for variant NM_000059.4(BRCA2):c.6057C>T (p.Asn2019=)

gnomAD frequency: 0.00102  dbSNP: rs147961615

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000210964	SCV000578004	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0061 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000123981	SCV000167376	benign	not specified	2013-10-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000210964	SCV000195995	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163115	SCV000213626	likely benign	Hereditary cancer-predisposing syndrome	2014-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001079310	SCV000252609	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163115	SCV000683750	likely benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679179	SCV000805733	likely benign	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000123981	SCV000859228	benign	not specified	2018-01-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679179	SCV000885101	benign	not provided	2017-07-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000210964	SCV001139134	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001079310	SCV002025791	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123981	SCV002070370	benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163115	SCV002536201	benign	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001079310	SCV004014907	benign	Hereditary breast ovarian cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123981	SCV004027448	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353589	SCV000592023	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn2019Asn variant was identified in 9 of 868 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs147961615) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar and Invitae; classified as likely benign by ClinVar), the ClinVar database (classified as benign by GeneDx, Invitae, MMGLUM; classified as likely benign by Ambry genetics) and UMD (28x with an “unclassified variant” classification). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Asn2019Asn variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 12 of 5000 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 19 of 4406 African American alleles, and the Exome Aggregation Consortium database (August 8, 2016) in 60 of 120608 chromosomes (freq. 0.0005) in the following populations: African in 59 of 10044 chromosomes (freq. 0.006) and Latino in 1 of 11568 chromosomes (freq. 0.00008), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Asn2019Asn variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679179	SCV001905993	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679179	SCV001930281	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000123981	SCV001958661	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679179	SCV001965624	likely benign	not provided		no assertion criteria provided	clinical testing