Peer-Reviewed Publication
Am J Hum Genet2026August 25, 2026Journal Article
RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.
Joanna Domènech-Vivó1, Hélène Tubeuf2, Romy L S Mesman3, Aurelie Drouet4, Mélanie Girardi4, María Concepción Alonso-Cerezo5, Diana Baralle6, Nadia Boutry-Kryza7, David J Bunyan8, Helen J Byers9, Sandrine M Caputo10, Kathleen B M Claes11, Miguel De la Hoya12, D Gareth Evans13, Laure Frésard14, Sophie Krieger15, Conxi Lázaro16, Mélanie Leone7, Eva Macháčková17, Mireia Menéndez18, Alejandro Moles-Fernández19, Gemma Montalban20, Erin Mundt21, Marcy E Richardson22, Elke M Van Veen9, Jamie Weyandt22, Judith Balmaña23, Amanda B Spurdle24, Orland Diez25, Maaike P G Vreeswijk3, Alexandra Martins4, Sara Gutiérrez-Enríquez26
1Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Programa de Doctorat en Biomedicina, Universitat de Barcelona (UB), Barcelona, Spain; Area of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
2University Rouen Normandie, Inserm U1245, 76000 Rouen, France; Interactive Biosoftware, Rouen, France.
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
4University Rouen Normandie, Inserm U1245, 76000 Rouen, France.
5Genética Clínica, Servicio de Oncología Médica, Hospital Universitario de la Princesa, Madrid, Spain.
6Faculty of Medicine, University of Southampton, Southampton, UK; University Hospital Southampton, Southampton, UK.
7Plateforme mixte de génétique moléculaire Hospices Civils de Lyon, Centre Léon Bérard, Lyon, France.
8Faculty of Medicine, University of Southampton, Southampton, UK; Wessex Genomics Laboratory Service (Salisbury), Salisbury District Hospital, Salisbury, UK.
9Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK; Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
10Service de Génétique, Institut Curie, 26 rue d'Ulm, Paris, France; Paris Sciences and Lettres (PSL) University, Paris, France.
11Center for Medical Genetics, Ghent University Hospital, Department of Biomolecular Medicine, Ghent University, CRIG (Cancer Research Institute Ghent), Ghent, Belgium.
12Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
13Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Division of Evolution and Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester Universities NHS Foundation Trust, Manchester, UK.
14Labcorp Genetics Inc, 1400 16th Street, San Francisco, CA, USA.
15University Rouen Normandie, Inserm U1245, 76000 Rouen, France; Laboratoire de Biologie et Génétique du Cancer, Centre François Baclesse, Caen, France; UNICAEN, Normandie Université, Caen, France.
16Hereditary Cancer Program, Oncobell, IDIBELL, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
17Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
18Hereditary Cancer Program, Oncobell, IDIBELL, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.
19Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Area of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
20Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
21Myriad Genetics, Inc., Salt Lake City, UT, USA.
22Ambry Genetics, Aliso Viejo, CA, USA.
23Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Medical Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
24QIMR Berghofer, Brisbane, QLD, Australia.
25Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Area of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
26Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Electronic address: sgutierrez@vhio.net.
Abstract
The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing prof…
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