Submissions for variant NM_000059.4(BRCA2):c.7806-40A>G

gnomAD frequency: 0.00858  dbSNP: rs9590939

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566840	SCV004101439	benign	BRCA2-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.7806-40A>G variant is an intronic variant occurring in intron 16 of the BRCA2 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.02867 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). This variant has been observed in >10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score >4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.008 (based on Pathology LR=0.81; Case-Control LR=0.0095), within the thresholds for Strong benign evidence (LR >=0.00285 & <0.05) (BP5_Strong met; Internal lab contributors). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BP7_Strong (RNA), BS2, BP5_Strong).
Invitae	RCV000045322	SCV000073335	benign	Hereditary breast ovarian cancer syndrome	2023-08-17	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113826	SCV000196009	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503364	SCV000592146	likely benign	not specified	2017-10-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001594826	SCV000602769	benign	not provided	2020-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001594826	SCV001828157	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	RCV000045322	SCV002025832	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113826	SCV004016865	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000503364	SCV004243065	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113826	SCV000147194	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-01-18	no assertion criteria provided	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000209000	SCV000265020	likely benign	Hereditary cancer-predisposing syndrome	2015-12-01	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000503364	SCV001906393	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000503364	SCV001951979	benign	not specified		no assertion criteria provided	clinical testing