Submissions for variant NM_000059.4(BRCA2):c.9257-16T>C

gnomAD frequency: 0.00597  dbSNP: rs11571818

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114078	SCV000245297	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 0.01055 (European), derived from 1000 genomes (2012-04-30).
Invitae	RCV000045764	SCV000073777	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000114078	SCV000154101	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-10	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000114078	SCV000196024	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152886	SCV000202306	benign	not specified	2015-10-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000152886	SCV000301782	benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045764	SCV000494375	benign	Hereditary breast ovarian cancer syndrome	2014-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000446929	SCV000537380	benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000468147	SCV000541044	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000114078	SCV000575764	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-22	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000152886	SCV000586991	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001573242	SCV000602757	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114078	SCV000743362	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114078	SCV000744560	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045764	SCV002025871	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798243	SCV002043698	benign	Breast and/or ovarian cancer	2021-04-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000152886	SCV002551845	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000446929	SCV002687639	benign	Hereditary cancer-predisposing syndrome	2014-09-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000114078	SCV004016856	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114078	SCV000147587	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114078	SCV000189322	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000152886	SCV000592269	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 c.9257-16T>C variant was identified in 121 of 53524 proband chromosomes (frequency: 0.002) from individuals or families with Breast and Ovarian cancer, and was present in 4 of 530 control chromosomes (frequency: 0.08) from healthy individuals (Caputo 2011, Borg 2010, Hadijisavvas 2003, Cvok 2008, Diez 2003). The variant was identified in dbSNP (ID: rs11571818) with “other” allele, with a minor allele frequency of 0.0044(1000 Genomes Project); in NHLBI Exome Sequencing Project (Exome Variant Server) in 67 of 8600 European and 10 of 4406 African Americans; in Exome Aggregation Consortium (ExAC) database in 574(3 homozygote) of 56204 of Europeans(non-Finnish), in 15 of 9522 Africans, in 25 of 10298 Latinos, in 116 (4 homozygote) of 15288 South Asians , in 77 (2 homozygote) of 6222 Europeans (Finnish) and 5 of 820 other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also found in LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, classified as benign by Invitae, as benign by Counsyl, as benign by GeneDX, as benign by Emory Genetics, as Likely benign by CHEO and as uncertain significance by BIC). It was also identified in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “likely benign” by a clinical laboratory), the BIC database (12X with no clinical importance), and UMD (73X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.5116G>A (p.Gly1706Arg), c.4391delC (p.Pro1464LeufsX2), c.81_134delp.Cys27X); BRCA2:c.6275_6276delTT (p.Leu2092ProfsX7), c.4889C>G (p.Ser1630X), increasing the likelihood that the c.9257-16T>C variant does not have clinical significance. The c.9257-16T>C 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 splicing studies (Bonnet 2008, Claes 2003) showed that the c.9257-16T>C do not result in aberrant splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000114078	SCV000733336	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573242	SCV001798803	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000152886	SCV001905684	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000152886	SCV001954160	benign	not specified		no assertion criteria provided	clinical testing