ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4986+3G>C (rs80358023)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048721 SCV000076734 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-08 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast and/or ovarian cancer (PMID: 29446198, 12491499, 23239986, 25971625, 18465347, 23772696, 25682074). This variant is also known as IVS16+3G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55341). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23239986). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000162881 SCV000213368 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing The c.4986+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been detected in several breast and/or ovarian cancer families as well as in a patient with triple negative breast cancer (Adem C et al. Cancer 2003 Jan; 97(1):1-11; Thomassen M et al. Acta Oncol. 2008;47(4):772-7; Singer CF et al. Clin Genet. 2014 Jan;85(1):72-5; Wong-Brown MW et al. Breast Cancer Res Treat. 2015 Feb;150(1):71-80; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). RT-PCR analysis of c.4986+3G>C revealed an alternate transcript with retention of 65 intronic nucleotides, and resulting in a premature termination codon (Wappenschmidt B et al. PLoS ONE 2012; 7(12):e50800). Of note, this alteration is also designated as IVS16+3G>C in published literature. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site and is predicted to weaken the efficacy of the native donor splice site by ESE finder. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl RCV000112443 SCV000221136 pathogenic Breast-ovarian cancer, familial 1 2015-02-13 criteria provided, single submitter literature only
GeneDx RCV000236214 SCV000292524 likely pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+3G>C or IVS15+3G>C and consists of a G>C nucleotide substitution at the +3 position of intron 15 of the BRCA1 gene. This variant is also known as BRCA1 5105+3G>C or IVS16+3G>C using alternate nomenclature. In vitro RNA analysis demonstrated that this variant causes aberrant splicing, resulting in an out-of-frame intron inclusion predicted to result in protein truncation (Wappenschmidt 2012). This variant has been observed in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Adem 2003, Thomassen 2008, Muendlein 2015, Wong-Brown 2015, Dudley 2018). BRCA1 c.4986+3G>C was not observed in large population cohorts (Lek 2016). The guanine (G) nucleotide that is altered is not conserved. Based on currently available evidence, we consider BRCA1 c.4986+3G>C to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112443 SCV000326080 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236214 SCV000605896 likely pathogenic not provided 2018-06-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162881 SCV000688528 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000236214 SCV000693496 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant occurs three bases after exon 15 of the BRCA1 gene. Experimental studies have shown that this variant causes aberrant splicing in vitro, resulting in an out-of-frame insertion predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (PMID: 23239986). This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 23239986, 12491499). This variant is also known as BRCA1 IVS16+3G>C and 5105G>C using alternate nomenclature. The mutation database ClinVar contains several entries for this variant (Variation ID: 55341).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000236214 SCV001447643 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000112443 SCV001499668 likely pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112443 SCV000145233 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048721 SCV000587438 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353420 SCV000591552 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 c.4986+3G>C variant was identified in 3 of 1748 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Muendlein 2015, Wong-Brown 2015). The variant was also identified in dbSNP (ID: rs80358023) as “With Pathogenic allele”, Clinvitae database (as uncertain significance by ClinVar and Invitae, as Pathogenic by ClinVar), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (as uncertain significance by Invitae, Ambry Genetics; as likely pathogenic by GeneDx; as pathogenic by Counsyl and BIC), the BIC database (11X with clinical importance).rnThe c.4986+3G>C 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. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, the variant was found in triple-negative patient in preclinical study by Wong-Brown (2015). The study suggests the variant leads to intronic retention of 65 bp and creates premature stop codon at position 1663 (p.Met1663ValfsX14) and classified it as likely pathogenic. 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 pathogenic role for this variant. This variant is classified as likely pathogenic.
Brotman Baty Institute,University of Washington RCV000112443 SCV001243312 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
King Laboratory,University of Washington RCV001171416 SCV001251321 pathogenic Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.