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The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Colombo M 1 , Lòpez-Perolio I 2 , Meeks HD 3 , Caleca L 1 , Parsons MT 4 , Li H 3 Show all authors , De Vecchi G 1 , Tudini E 4 , Foglia C 1 , Mondini P 1 , Manoukian S 5 , Behar R 2 , Garcia EBG 6 , Meindl A 7 , Montagna M 8 , Niederacher D 9 , Schmidt AY 10 , Varesco L 11 , Wappenschmidt B 12 , Bolla MK 13 , Dennis J 13 , Michailidou K 13 , Wang Q 13 , Aittomäki K 14 , Andrulis IL 15 , Anton-Culver H 16 , Arndt V 17 , Beckmann MW 18 , Beeghly-Fadel A 19 , Benitez J 20 , Boeckx B 21 , Bogdanova NV 22 , Bojesen SE 23 , Bonanni B 24 , Brauch H 25 , Brenner H 17 , Burwinkel B 26 , Chang-Claude J 27 , Conroy DM 28 , Couch FJ 29 , Cox A 30 , Cross SS 31 , Czene K 32 , Devilee P 33 , Dörk T 34 , Eriksson M 32 , Fasching PA 18 , Figueroa J 35 , Fletcher O 36 , Flyger H 37 , Gabrielson M 32 , García-Closas M 38 , Giles GG 39 , González-Neira A 20 , Guénel P 40 , Haiman CA 41 , Hall P 32 , Hamann U 42 , Hartman M 43 , Hauke J 12 , Hollestelle A 44 , Hopper JL 45 , Jakubowska A 46 , Jung A 27 , Kosma VM 47 , Lambrechts D 21 , Le Marchand L 48 , Lindblom A 49 , Lubinski J 46 , Mannermaa A 47 , Margolin S 50 , Miao H 43 , Milne RL 39 , Neuhausen SL 51 , Nevanlinna H 52 , Olson JE 53 , Peterlongo P 54 , Peto J 55 , Pylkäs K 56 , Sawyer EJ 57 , Schmidt MK 58 , Schmutzler RK 12 , Schneeweiss A 26 , Schoemaker MJ 59 , See MH 60 , Southey MC 61 , Swerdlow A 59 , Teo SH 60 , Toland AE 62 , Tomlinson I 63 , Truong T 40 , van Asperen CJ 64 , van den Ouweland AMW 65 , van der Kolk LE 66 , Winqvist R 56 , Yannoukakos D 67 , Zheng W 19 , kConFab/AOCS Investigators 68 , Dunning AM 28 , Easton DF 13 , Henderson A 69 , Hogervorst FBL 66 , Izatt L 70 , Offitt K 71 , Side LE 72 , van Rensburg EJ 73 , Embrace S 74 , Hebon S 75 , McGuffog L 13 , Antoniou AC 13 , Chenevix-Trench G 4 , Spurdle AB 4 , Goldgar DE 3 , Hoya M 2 , Radice P 1

Affiliations 

  • 1 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 2 Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 3 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
  • 4 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
  • 5 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 6 Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
  • 7 Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany
  • 8 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
  • 9 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Duesseldorf, Germany
  • 10 Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 11 Hereditary Cancer Unit, IRCCS AOU San Martino -IST, Genova, Italy
  • 12 Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
  • 13 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 14 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 15 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario
  • 16 Department of Epidemiology, University of California Irvine, Irvine, California
  • 17 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 18 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 19 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 20 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 21 VIB Center for Cancer Biology, VIB, Leuven, Belgium
  • 22 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 23 Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 24 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
  • 25 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 26 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 27 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 28 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 29 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, New York
  • 30 Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
  • 31 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 32 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 33 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 34 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 35 Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK
  • 36 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
  • 37 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 38 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
  • 39 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia
  • 40 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 41 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 42 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
  • 43 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 44 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 45 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia
  • 46 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 47 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
  • 48 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
  • 49 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 50 Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  • 51 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California
  • 52 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 53 Department of Health Sciences Research, Mayo Clinic, Rochester, New York
  • 54 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 55 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  • 56 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
  • 57 Research Oncology, Guy's Hospital, King's College London, London, UK
  • 58 Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 59 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 60 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 61 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 62 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • 63 Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
  • 64 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 65 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 66 Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 67 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece
  • 68 Peter MacCallum Cancer Center, Melbourne, Australia
  • 69 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
  • 70 Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK
  • 71 Clinical Genetics Research Laboratory, Dept. of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 72 Wessex Clinical Genetics Service, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA
  • 73 Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Pretoria, South Africa
  • 74 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
  • 75 The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating center: Netherlands Cancer Institute, Amsterdam, The Netherlands
Hum Mutat, 2018 May;39(5):729-741.
PMID: 29460995 DOI: 10.1002/humu.23411

Abstract

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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