Submissions for variant NM_007294.4(BRCA1):c.5074+6C>G

gnomAD frequency: 0.00002  dbSNP: rs80358032

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077153	SCV001161602	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 5.98E-08
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205845	SCV000259518	benign	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077153	SCV000267717	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000077153	SCV000487958	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000447045	SCV000537480	likely benign	Hereditary cancer-predisposing syndrome	2016-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501126	SCV000918720	benign	not specified	2017-11-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5074+6C>G variant involves the alteration of a non-conserved intronic nucleotide. MutationTaster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. Functional studies confirmed that this variant has no effect on splicing (Bonatti_2006, Houdayer_2011, Steffensen_2014). This variant was found in 16/276994 control chromosomes (gnomAD) at a frequency of 0.0000578, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple HBOC patients in literature without cosegregation and co-occurrence evidence. In a clinical database (UMD), this variant is reported to co-occur with two deleterious variants in BRCA1 (c.4327C>T (p.Arg1443X) and c.1088delA (p.Asn363IlefsX11)), strongly supporting a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Mendelics	RCV000077153	SCV001140491	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000501126	SCV001470006	benign	not specified	2021-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000656627	SCV001891516	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30209399)
Sema4, Sema4	RCV000447045	SCV002537808	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000501126	SCV002550957	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656627	SCV004811492	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BRCA1: BP4
All of Us Research Program, National Institutes of Health	RCV000077153	SCV004815201	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077153	SCV000108950	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-02-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077153	SCV000145292	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656627	SCV000591569	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1, c.5074+6C>G variant was identified in 1 of 552 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Bonatti 2006). The variant was also identified in dbSNP (ID: rs80358032), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as an uncertain significance by BIC), GeneInsight VariantWire database (2X, classified as IARC 3 and Benign by clinical laboratories), the BIC database (2X with unknown clinical importance) and UMD (6X as a likely neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.4327C>T (p.Arg1443X)), increasing the likelihood that the c.5074+6C>G variant does not have clinical significance. This variant was identified in the Exome Variant Server project in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 7 of 66484 chromosomes (frequency: 0.00001) from a population of European (Non-Finnish) individuals, 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 c.5074+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. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. An RNA-based study by Bonatti (2006) found that the variant showed the same pattern in RT-PCR product as normal controls, suggesting that this variant expresses a normal mRNA transcript which would likely be translated into a wild-type protein. However, functional study by Steffensen (2014) identified minor increase in skipping of exon 17; minor increase in the transcripts lacking exon 17 compared with the wild type and classifies this variant as a VUS. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656627	SCV000778734	likely benign	not provided	2016-12-28	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735560	SCV000863698	likely benign	Breast and/or ovarian cancer	2013-10-07	no assertion criteria provided	clinical testing
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000205845	SCV000916355	benign	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077153	SCV001243471	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000656627	SCV001906317	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000656627	SCV001930809	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000501126	SCV001956818	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000501126	SCV001969002	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077153	SCV004243953	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing