Submissions for variant NM_007294.4(BRCA1):c.5406+8T>C

gnomAD frequency: 0.00514  dbSNP: rs55946644

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112640	SCV000244535	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02033 (African), derived from 1000 genomes (2012-04-30).
Counsyl	RCV000112640	SCV000220276	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-28	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000168523	SCV000227831	benign	not specified	2014-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000204121	SCV000262328	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000210819	SCV000267001	benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112640	SCV000403054	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-07-23	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204121	SCV000494360	benign	Hereditary breast ovarian cancer syndrome	2014-04-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000458390	SCV000540968	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000112640	SCV000575718	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-07	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000168523	SCV000586911	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210819	SCV000683310	benign	Hereditary cancer-predisposing syndrome	2015-06-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112640	SCV000744583	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000168523	SCV000806972	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170588	SCV001333176	benign	Breast and/or ovarian cancer	2017-11-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705817	SCV001472554	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001705817	SCV001861389	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30209399)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000204121	SCV002025899	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168523	SCV002065758	benign	not specified	2021-02-15	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000204121	SCV002515233	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000210819	SCV002537853	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168523	SCV002550941	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210819	SCV002653512	benign	Hereditary cancer-predisposing syndrome	2014-07-21	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	RCV000112640	SCV004016767	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112640	SCV000145495	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353492	SCV000591625	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.5406+8T>C variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSBP (ID: rs55946644) as other, ClinVar (8x benign: ENIGMA, Invitae, Vantari Genetics, LabCorp, Baylor Miraca Genetics, Counsyl, Emory Genetics, BIC; 2x likely benign: Illumina, CHEO), Genesight-COGR (classified as benign by a clinical laboratory), LOVD 3.0 (7 entries, 2x predicted neutral, 1x no splicing defect), BIC Database (16x not pathogenic/low clinical significance, MAF>0.01) databases. The variant was not identified in the COSMIC, MutDB, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was also identified by our laboratory in 2 individuals with breast cancer. The variant was identified in control databases in 400 of 277096 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 351 of 24014 chromosomes (freq: 0.015). Functional studies using splicing reporter minigene assays and patient RNA analysis indicate no effect on splicing (Steffensen 2014, Bonnet 2008, Thery 2011, Houdayer 2012). 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 summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000210819	SCV000787911	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112640	SCV001238703	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168523	SCV001905717	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168523	SCV001951160	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168523	SCV002035519	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112640	SCV004243917	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing