Submissions for variant NM_000059.4(BRCA2):c.7805+6C>G

gnomAD frequency: 0.00290  dbSNP: rs81002819

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045315	SCV000073328	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000077412	SCV000154087	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-03-18	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000174984	SCV000226399	benign	not specified	2014-08-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077412	SCV000267810	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045315	SCV000494369	benign	Hereditary breast ovarian cancer syndrome	2014-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103725	SCV000602796	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580581	SCV000683909	benign	Hereditary cancer-predisposing syndrome	2015-03-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174984	SCV000805768	benign	not specified	2017-03-20	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045315	SCV002025829	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000174984	SCV002070583	likely benign	not specified	2020-10-27	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000045315	SCV002515149	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000580581	SCV002531884	benign	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149691	SCV003838177	likely benign	Breast and/or ovarian cancer	2022-05-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077412	SCV000109210	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077412	SCV000147186	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000174984	SCV000592144	benign	not specified		no assertion criteria provided	clinical testing	The c.7805+6C>G variant was shown to produce a wildtype transcript in an m RNA based assay using lymphocyte cell lines of variant carriers, who met requirements for clinical testing or research into familial aspects of breast cancer; with aberrant in vitro transcripts accurately predicted by splice prediction programs (Whiley 2011). The variant was also identified in dbSNP (ID: rs81002819) “With other allele”, with a minor allele frequency of 0.001 (1000 Genomes Project), and the BIC database (19X with unknown clinical importance). The variant was identified by the Exome Variant Server project in 43 of 4406 African American alleles (frequency: 0.01). The variant was identified in UMD (12X as an unclassified variant) with co-occurring pathogenic variants: BRCA1 c.3607C>T (p.Arg1203X), BRCA2 c.7679_7680delTT (p.Phe2560SerfsX5), and BRCA2 c.2627delA (p.Asn876IlefsX19, increasing the likelihood that the c.7805+6C>G variant does not have clinical significance. The variant was also identified by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) 2X (1X by multiple submitters (SCRP as benign, and BIC as uncertain) and 1X by Invitae, classification not provided). The c.7805+6C>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratoy’s criteria to be classified as benign.