ClinVar Miner

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

dbSNP: rs80358023
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000048721 SCV000076734 pathogenic Hereditary breast ovarian cancer syndrome 2024-12-13 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12491499, 18465347, 23239986, 23772696, 25682074, 25971625, 29446198). This variant is also known as IVS16+3G>C. ClinVar contains an entry for this variant (Variation ID: 55341). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice acceptor, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23239986, 31843900). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162881 SCV000213368 pathogenic Hereditary cancer-predisposing syndrome 2023-01-10 criteria provided, single submitter clinical testing The c.4986+3G>C intronic pathogenic mutation 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; Dudley B et al. Cancer, 2018 04;124:1691-1700; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RT-PCR analysis of c.4986+3G>C revealed an alternate transcript with retention of 65 intronic nucleotides resulting in a premature termination codon (Ambry internal data; Wappenschmidt B et al. PLoS ONE 2012; 7(12):e50800). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as IVS16+3G>C in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000112443 SCV000221136 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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 Diagnostics, LLC DBA Color Health RCV000162881 SCV000688528 likely pathogenic Hereditary cancer-predisposing syndrome 2024-05-07 criteria provided, single submitter clinical testing This variant causes a G>C nucleotide substitution at the +3 position of intron 15 of the BRCA1 gene. RNA studies have observed aberrant splicing in carrier RNA that is expected to result in an absent or non-functional protein product (PMID: 23239986, 31843900). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in at least five individuals affected with breast, ovarian and pancreatic cancer (PMID: 12491499, 25682074, 25971625, 29360161, 35409996) and in suspected hereditary breast and ovarian cancer families (PMID: 18465347, 23772696). However, a multifactorial analysis has reported contradictory low segregation likelihood ratio for pathogenicity (LR) of 0.0001 and high tumor pathology LR of 418.5086 for this variant (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
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, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048721 SCV001774695 pathogenic Hereditary breast ovarian cancer syndrome 2021-07-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4986+3G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wappenschmidt_2012). The variant was absent in 249776 control chromosomes (gnomAD). c.4986+3G>C has been reported in the literature in multiple individuals affected with breast and ovarian cancers (example: Rebbeck_2018, Wappenschmidt_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting a loss on protein function (Findlay_2018). 12 ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center RCV000112443 SCV002581629 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-11 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000236214 SCV003917925 pathogenic not provided 2023-01-01 criteria provided, single submitter clinical testing BRCA1: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Baylor Genetics RCV000112443 SCV004217009 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-05 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000048721 SCV005045789 pathogenic Hereditary breast ovarian cancer syndrome 2023-11-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004804013 SCV005426852 pathogenic BRCA1-related cancer predisposition 2024-04-02 criteria provided, single submitter clinical testing The variant c.4986+3G>C in the BRCA1 gene is located in intron 15 and is predicted to result in aberrant splicing and a disrupted or absent protein product (SpliceAI donor loss score 0.93). This variant (also known as IVS16+3G>C) has been observed in multiple individuals with breast cancer, triple negative breast cancer, ovarian cancer, pancreatic cancer, or suspected breast and ovarian cancer (PMID: 12491499, 18465347, 23239986, 23772696, 25682074, 25971625, 29360161, 29446198, 30322717). Experimental studies have shown that this variant results in retention of 65 intronic nucleotides and leads to the protein change p.Met1663Valfs*14 (PMID: 23239986). Functional studies have also shown this variant to result in loss of function with impact on haploid cell survival (PMID: 30209399). This variant is absent in the general population database, gnomAD. Truncating variants in BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112443 SCV000145233 pathogenic Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 1 no assertion provided in vitro
King Laboratory, University of Washington RCV001171416 SCV001251321 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome 2019-09-01 no assertion criteria provided research
BRCAlab, Lund University RCV000112443 SCV004243965 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000048721 SCV005374634 likely pathogenic, low penetrance Hereditary breast ovarian cancer syndrome 2024-10-10 no assertion criteria provided curation Taking into accout the results of the splice analysis and the low LRs from segregation analysis we assume that this variant is likely to be a variant with reduced penetrance in comparision with other LOF-variants in BRCA1; According to the ClinGen ENIGMA BRCA1 v1.1.0 criteria we chose these criteria: PS1 (medium pathogenic): Apply PS1_Moderate, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. Various variants in this splice site are classified as pathogenic e.g. c.4986+6T>G; +1/2, PS3 (strong pathogenic): Findlay et al. (PS3 met as per ENIGMA/ClinGen table 9), PM2 (supporting pathogenic): not in gnomAD (90 families in GC-HBOC), PP3 (supporting pathogenic): Variant is predicted to have a splice effect by SpliceAI (threshold: 0.2, value: 0.93).

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.