ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074+6C>G (rs80358032)

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Total submissions: 15
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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 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
Invitae RCV000205845 SCV000259518 benign Hereditary breast and ovarian cancer syndrome 2020-11-05 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000077153 SCV000267717 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000077153 SCV000487958 uncertain significance Breast-ovarian cancer, familial 1 2015-12-10 criteria provided, single submitter clinical testing
Color Health, Inc 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 1 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656627 SCV001470006 likely benign not provided 2019-12-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077153 SCV000108950 benign Breast-ovarian cancer, familial 1 2009-02-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077153 SCV000145292 uncertain significance Breast-ovarian cancer, familial 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 and 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 1 no assertion provided in vitro

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