Submissions for variant NM_000059.4(BRCA2):c.8487+47C>T

dbSNP: rs11571744

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113946	SCV000245178	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.05488 (African), derived from 1000 genomes (2012-04-30).
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113946	SCV000196015	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113946	SCV000743347	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001668216	SCV001884061	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002222168	SCV002025853	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000499878	SCV002551823	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113946	SCV004016858	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001668216	SCV005236535	benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113946	SCV000147379	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1998-11-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499878	SCV000592201	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 c.8487+47C>T variant was identified in the literature. The variant was also identified in dbSNP (ID: rs11571744) “With Uncertain significance allele”, with a minor allele frequency of 0.0162 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database (X1), LOVD, the ClinVar database, GeneInsight COGR database (1X), the BIC database (2X with no clinical importance), and UMD (37X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 (c.1813dup (p.Ile605AsnfsX11); c.5576_5579delTTAA (p.Ile1859LysfsX3); c.1310_1313delAAGA (p.Lys437IlefsX22); BRCA2 (c.IVS16+6T>C (c.4986+6T>C); c.1488delT (p.Leu498SerfsX5)), increasing the likelihood that the c.8487+47C>T variant does not have clinical significance. In BIC database variant was reported to occur in outbred control reference groups at an allele frequency >1% (MAF>0.01), and classifies the variant as not pathogenic/low clinical significance. This variant was identified in the 1000 Genomes Project in 81 of 5000 chromosomes (frequency: 0.0162), Exome Variant Server project in 1 of 8600 European American and in 197 of 4404 African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 436 of 9658 chromosomes (frequency: 0.045) and nine times in homozygous state from a population of African individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in 39 of 91040 European (Non-Finnish)/ Latino / South Asian/European (Finnish) individuals, increasing the likelihood this could be a low frequency benign variant. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, global sequence diversity analysis identified the variant has global heterozygosity 0.018 and classified the variant as polymorphism (Wagner 1999). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000499878	SCV001906084	benign	not specified		no assertion criteria provided	clinical testing