ArticleHuman molecular genetics2016
Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.
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Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed.
- Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions.European journal of human genetics : EJHG · 2026Review
- Generation of functional noncanonical donor splice sites by +2T variants in breast cancer susceptibility genes: impact on clinical interpretation.The Journal of pathology · 2026Article
- A Plot Twist: When RNA Yields Unexpected Findings in Paired DNA-RNA Germline Genetic Testing.Genes · 2025Article
- Functional characterization of BRCA1 variants of unknown significance using homologous recombination repair assays.Breast cancer research : BCR · 2025Article
- Bridging the Diagnostic Gap in Hereditary Cancers with Simple, Cost-Effective, High-Throughput RNA Splicing Analysis.The Journal of molecular diagnostics : JMD · 2025Article
- RNA-based diagnostic studies in genetics: Review and guidance from a multidisciplinary French network.European journal of human genetics : EJHG · 2025Review
- The SeqSplice multiplexed minigene splicing assay for characterization and quantitation of variant-inducedGenome research · 2025Article
- Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.Nature communications · 2025Article
- Genetic modulation of RNA splicing rescues BRCA2 function in mutant cells.Life science alliance · 2025Article
- Multifocal Retinocytoma Associated With Intronic Acceptor Splice Site Variants in the RB1 Gene.Cureus · 2024Article
- Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.American journal of human genetics · 2024Article
- Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.American journal of human genetics · 2024Article
- Article
- Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.Breast cancer research : BCR · 2024Article
- Tracking updates in clinical databases increases efficiency for variant reanalysis.Genetics in medicine open · 2024Article
- Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup.American journal of human genetics · 2023Article
- Optimising clinical care throughJournal of medical genetics · 2023Article
- APPLICATION OF THE ACMG/AMP FRAMEWORK TO CAPTURE EVIDENCE RELEVANT TO PREDICTED AND OBSERVED IMPACT ON SPLICING: RECOMMENDATIONS FROM THE CLINGEN SVI SPLICING SUBGROUP.medRxiv : the preprint server for health sciences · 2023Article
- Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.Human mutation · 2022Article
- Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.Cancer research and treatment · 2022Article
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Authors and funding
75 authors.
Miguel de la HoyaMolecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain amanda.spurdle@qimr.edu.au mhoya@hotmail.com.
Omar SoukariehInserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
Irene López-PerolioMolecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.
Ana VegaFundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
Logan C WalkerDepartment of Pathology, University of Otago, Christchurch 8140, New Zealand.
Yvette van IerlandDepartment of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.
Diana BaralleHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.
Marta SantamariñaCIBERER, Grupo de Medicina Xenómica-USC, Universidade de Santiago de Compostela, Fundacion Galega de Medicina Xenómica (SERGAS), Santiago de Compostela 15706, Spain.
Vanessa LattimoreDepartment of Pathology, University of Otago, Christchurch 8140, New Zealand.
Juul WijnenDepartment of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands Department of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.
Philip WhileyDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Ana BlancoFundacion Publica Galega de Medicina Xenómica-SERGAS Grupo de Medicina Xenómica-USC, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
Michela RaponiHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton S016 5YA, UK.
Jan HaukeCenter for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.
Barbara WappenschmidtCenter for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.
Alexandra BeckerCenter for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hosptial Cologne, Cologne 50931, Germany.
Thomas V O HansenCenter for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen DK-2100, Denmark.
Raquel BeharMolecular Oncology Laboratory, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain.
KConFaB InvestigatorsPeter MacCallum Cancer Center, University of Melbourne, Melbourne, VIC 3002, Australia.
Diether NiederacherDepartment of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf 40225, Germany.
Norbert ArnoldDepartment of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel 24105, Germany.
Bernd DworniczakInstitute of Human Genetics, University of Münster, Münster 48149, Germany.
Doris SteinemannInstitute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.
Ulrike FaustInstitute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen 72076, Germany.
Wendy RubinsteinNational Institutes of Health, Bethesda, MD 20892-2152, USA.
Peter J HulickCenter for Medical Genetics, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA.
Claude HoudayerService de Génétique, Department de Biologie des Tumeurs, Institut Curie and INSERM U830, Centre de Recherche de l'Institut Curie, Paris, and Universite Paris Descartes, Sorbonne Paris Cite, Paris 75248, France.
Sandrine M CaputoService de Génétique, Department de Biologie des Tumeurs, Institut Curie, Paris 75248, France.
Laurent CasteraCentre Francois Baclesse, Laboratoire de Biologie et de Genetique du Cancer, 14076 Caen, Paris 75248, France.
Tina PesaranAmbry Genetics, Aliso Viejo, CA 92656, USA.
Elizabeth ChaoAmbry Genetics, Aliso Viejo, CA 92656, USA.
Carole BrewerDepartment of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK.
Melissa C SoutheyGenetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
Christi J van AsperenDepartment of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.
Christian F SingerDepartment of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.
Jan SullivanGenetic Health Service NZ, South Island Hub, Christchurch Hospital, Christchurch 8140, New Zealand.
Nicola PoplawskiAdult Genetics Unit, South Australian Clinical Genetics Service, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA 5067, Australia University Department of Paediatrics, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia.
Phuong MaiClinical Genetics Branch, DCEG, NCI, NIH, Bethesda, MD, USA.
Julian PetoLondon School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
Nichola JohnsonBreakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, UK.
Barbara BurwinkelMolecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.
Harald SurowyMolecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany.
Stig E BojesenCopenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen 2730, Denmark Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1165, Denmark.
Henrik FlygerDepartment of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Denmark.
Annika LindblomDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Sara MargolinDepartment of Oncology Pathology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Jenny Chang-ClaudeDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Anja RudolphDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
Paolo RadiceUnit of "Molecular bases of genetic risk and genetic testing", Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20139, Italy.
Laura GalastriAssociazione Volontari Italiani Sangue (AVIS) comunale di Milano, Milano 20139, Italy.
Janet E OlsonDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Emily HallbergDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Graham G GilesCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.
Roger L MilneCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC 3010, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.
Irene L AndrulisLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, M5B 1W8, Canada.
Gord GlendonLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Per HallDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Kamila CzeneDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Fiona BlowsCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
Mitul ShahCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
Qin WangCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Joe DennisCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Kyriaki MichailidouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.
Lesley McGuffogCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Manjeet K BollaCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Antonis C AntoniouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Douglas F EastonCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
Fergus J CouchDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Sean TavtigianDepartment of Oncological Sciences.
Maaike P VreeswijkDepartment of Clinical Genetics, Leiden University Medical Centre, Leiden 2300, The Netherlands.
Michael ParsonsDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Huong D MeeksDepartment of Oncological Sciences.
Alexandra MartinsInserm U1079-IRIB, University of Rouen, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
David E GoldgarDepartment of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Amanda B SpurdleDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia amanda.spurdle@qimr.edu.au mhoya@hotmail.com.
Funding
The Role of CHFR in Tumorigenesis and Paclitaxel-Sensitivity in Breast CancerP50CA116201 · NCI · MAYO CLINIC ROCHESTER · PI PETER C LUCAS · 2005 to 2026
$49.9MBreast Cancer Family Registry CohortUM1CA164920 · NCI · CANCER PREVENTION INSTIT OF CALIFORNIA · PI ANDRULIS, IRENE, BUYS, SAUNDRA S · 2012 to 2017
$12.7MEpidemiologic StudiesU19CA148065 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI AHSAN, HABIBUL, BRUGGE, JOAN SIEFERT · 2010 to 2014
$10.6MEpidemiological and Clinical Translational Studies Post Genome-Wide AssociationU19CA148537 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI EASTON, DOUGLAS FREDERICK, EELES, ROSALIND · 2010 to 2014
$10.4MOvarian cancer GWAS discovery, expansion and replication (N2 - Project #1)U19CA148112 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SELLERS, THOMAS A · 2010 to 2014
$10.2MA genome-wide association study for breast cancer in BRCA1 mutation carriersR01CA128978 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2008 to 2012
$4.8MBRCA1 and BRCA2 missense mutations and breast cancer riskU01CA116167 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2013 to 2017
$2.7MCancer Research UK 10118Cancer Research UK 11174Cancer Research UK 20861NCI NIH HHS P50 CA116201NCI NIH HHS R01 CA128978NCI NIH HHS U01 CA116167NCI NIH HHS U19 CA148065NCI NIH HHS U19 CA148112NCI NIH HHS U19 CA148537NCI NIH HHS UM1 CA164920
Abstract
A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10
Indexed as
AdultAgedAlternative SplicingBRCA1 ProteinBreast NeoplasmsDNA Mutational AnalysisExonsFemaleGene Expression Regulation, NeoplasticHumansMiddle AgedMutationOvarian NeoplasmsRNA Splice SitesRNA SplicingTumor Suppressor ProteinsBRCA1 ProteinRNA Splice SitesTumor Suppressor Proteins
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