Submissions for variant NM_000059.4(BRCA2):c.7435+6G>A

gnomAD frequency: 0.00053  dbSNP: rs81002852

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167780	SCV000073224	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000168598	SCV000167393	benign	not specified	2013-10-30	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768633	SCV000219392	likely benign	Breast and/or ovarian cancer	2022-09-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031678	SCV000220684	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-10	criteria provided, single submitter	literature only
Vantari Genetics	RCV000210777	SCV000267022	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168598	SCV000593729	likely benign	not specified	2016-08-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000168598	SCV000600749	benign	not specified	2022-04-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210777	SCV000683872	benign	Hereditary cancer-predisposing syndrome	2016-01-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000210777	SCV000803156	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000031678	SCV001139179	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679187	SCV001746175	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167780	SCV002025817	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167780	SCV002515145	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000210777	SCV002531856	likely benign	Hereditary cancer-predisposing syndrome	2021-04-16	criteria provided, single submitter	curation
Ambry Genetics	RCV000210777	SCV002672571	likely benign	Hereditary cancer-predisposing syndrome	2015-02-28	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167780	SCV004014896	benign	Hereditary breast ovarian cancer syndrome	2023-06-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168598	SCV004027472	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031678	SCV000054285	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-02-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031678	SCV000147083	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000168598	SCV000587893	uncertain significance	not specified	2014-12-23	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168598	SCV000592108	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 c.7435+6G>A variant was identified in 2 of 124 proband chromosomes (frequency: 0.016) from individuals or families with hereditary breast or ovarian cancer (Thomassen 2012, Whiley 2011); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs81002852) “With other allele” in the 1000 Genomes Project in 3 of 3000 chromosomes (frequency: 0.001), Exome Variant Server project in 12 of 4404 African American alleles, 0.0027), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also found in the ClinVar database with conflicting data from submitters, the BIC database (14 X with unknown clinical importance), and UMD (13 X as an unknown variant). In UMD the variant was identified with one co-occurring pathogenic BRCA1 variant c.2477_2478delCA (p.Thr826ArgfsX4) and one co-occuring BRCA2 pathogenic variant c.48dup (p.Thr17AspfsX14), increasing the likelihood that the c.7435+6G>A variant does not have clinical significance. The c.7435+6G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. In addition, in vitro analysis of mRNA in two studies indicated no splicing alterations (Thomassen 2012, Whiley 2011). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004528144	SCV000805762	likely benign	BRCA2-related disorder	2019-04-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000167780	SCV000916365	benign	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679187	SCV001951991	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679187	SCV001968186	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679187	SCV002035551	likely benign	not provided		no assertion criteria provided	clinical testing