. 2016 May;53(5):298-309.

doi: 10.1136/jmedgenet-2015-103529. Epub 2016 Feb 26.

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Douglas F Easton¹, Fabienne Lesueur², Brennan Decker³, Kyriaki Michailidou⁴, Jun Li⁵, Jamie Allen⁶, Craig Luccarini⁷, Karen A Pooley⁶, Mitul Shah⁷, Manjeet K Bolla⁶, Qin Wang⁶, Joe Dennis⁶, Jamil Ahmad⁸, Ella R Thompson⁹, Francesca Damiola¹⁰, Maroulio Pertesi⁸, Catherine Voegele⁸, Noura Mebirouk², Nivonirina Robinot⁸, Geoffroy Durand⁸, Nathalie Forey⁸, Robert N Luben¹¹, Shahana Ahmed⁷, Kristiina Aittomäki¹², Hoda Anton-Culver¹³, Volker Arndt¹⁴; Australian Ovarian Cancer Study Group; Caroline Baynes⁷, Matthias W Beckman¹⁵, Javier Benitez¹⁶, David Van Den Berg¹⁷, William J Blot¹⁸, Natalia V Bogdanova¹⁹, Stig E Bojesen²⁰, Hermann Brenner²¹, Jenny Chang-Claude²², Kee Seng Chia²³, Ji-Yeob Choi²⁴, Don M Conroy⁷, Angela Cox²⁵, Simon S Cross²⁶, Kamila Czene²⁷, Hatef Darabi²⁷, Peter Devilee²⁸, Mikael Eriksson²⁷, Peter A Fasching²⁹, Jonine Figueroa³⁰, Henrik Flyger³¹, Florentia Fostira³², Montserrat García-Closas³³, Graham G Giles³⁴, Gord Glendon³⁵, Anna González-Neira³⁶, Pascal Guénel³⁷, Christopher A Haiman¹⁷, Per Hall²⁷, Steven N Hart³⁸, Mikael Hartman³⁹, Maartje J Hooning⁴⁰, Chia-Ni Hsiung⁴¹, Hidemi Ito⁴², Anna Jakubowska⁴³, Paul A James⁴⁴, Esther M John⁴⁵, Nichola Johnson⁴⁶, Michael Jones⁴⁷, Maria Kabisch⁴⁸, Daehee Kang⁴⁹; kConFab Investigators; Veli-Matti Kosma⁵⁰, Vessela Kristensen⁵¹, Diether Lambrechts⁵², Na Li⁵³; Lifepool Investigators; Annika Lindblom⁵⁴, Jirong Long⁵⁵, Artitaya Lophatananon⁵⁶, Jan Lubinski⁴³, Arto Mannermaa⁵⁰, Siranoush Manoukian⁵⁷, Sara Margolin⁵⁸, Keitaro Matsuo⁵⁹, Alfons Meindl⁶⁰, Gillian Mitchell⁶¹, Kenneth Muir⁶²; NBCS Investigators; Ines Nevelsteen⁶³, Ans van den Ouweland⁶⁴, Paolo Peterlongo⁶⁵, Sze Yee Phuah⁶⁶, Katri Pylkäs⁶⁷, Simone M Rowley⁶⁸, Suleeporn Sangrajrang⁶⁹, Rita K Schmutzler⁷⁰, Chen-Yang Shen⁷¹, Xiao-Ou Shu⁷², Melissa C Southey⁷³, Harald Surowy⁷⁴, Anthony Swerdlow⁷⁵, Soo H Teo⁶⁶, Rob A E M Tollenaar⁷⁶, Ian Tomlinson⁷⁷, Diana Torres⁷⁸, Thérèse Truong³⁷, Celine Vachon³⁸, Senno Verhoef⁷⁹, Michelle Wong-Brown⁸⁰, Wei Zheng⁵⁵, Ying Zheng⁸¹, Heli Nevanlinna⁸², Rodney J Scott⁸³, Irene L Andrulis⁸⁴, Anna H Wu¹⁷, John L Hopper⁸⁵, Fergus J Couch⁸⁶, Robert Winqvist⁶⁷, Barbara Burwinkel⁷⁴, Elinor J Sawyer⁸⁷, Marjanka K Schmidt⁷⁹, Anja Rudolph⁸⁸, Thilo Dörk⁸⁹, Hiltrud Brauch⁹⁰, Ute Hamann⁴⁸, Susan L Neuhausen⁹¹, Roger L Milne³⁴, Olivia Fletcher⁴⁶, Paul D P Pharoah¹, Ian G Campbell⁹², Alison M Dunning⁷, Florence Le Calvez-Kelm⁸, David E Goldgar⁹³, Sean V Tavtigian⁹⁴, Georgia Chenevix-Trench⁵

Affiliations

¹ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
² Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, Paris, France.
³ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Cancer Genetics and Comparative Genomics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁵ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁷ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁸ Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
⁹ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
¹⁰ Genetic of Breast Cancer Team, Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France.
¹¹ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹³ Department of Epidemiology, University of California Irvine, Irvine, California, USA.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
¹⁶ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
¹⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁸ International Epidemiology Institute, Rockville, Maryland, USA Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁰ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁴ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
²⁵ Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
²⁶ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
²⁹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles, California, USA.
³⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
³¹ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece.
³³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
³⁴ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁵ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
³⁶ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
³⁷ University Paris-Sud, UMRS 1018, Villejuif, France Inserm, CESP Center for research in Epidemiology and Population Health, U1018, Cancer & Environment Group, Villejuif, France.
³⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
³⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore Department of Surgery, National University Health System, Singapore, Singapore.
⁴⁰ Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁴¹ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴² Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
⁴³ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁴⁴ Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴⁵ Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California, USA Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁴⁶ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁴⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁴⁸ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁹ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University, Seoul, Korea.
⁵⁰ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
⁵¹ Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), Oslo, Norway.
⁵² Vesalius Research Center, VIB, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
⁵³ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁵⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁵⁵ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁵⁶ Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK.
⁵⁷ Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.
⁵⁸ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
⁵⁹ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁶⁰ Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
⁶¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁶² Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK Institute of Population Health, University of Manchester, Manchester, UK.
⁶³ University Hospital Gashuisberg, Leuven, Belgium.
⁶⁴ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁵ IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
⁶⁶ Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
⁶⁷ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁶⁸ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
⁶⁹ National Cancer Institute, Bangkok, Thailand.
⁷⁰ Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany Medical Faculty, Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
⁷¹ School of Public Health, China Medical University, Taichung, Taiwan Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁷² Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁷³ Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁴ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁷⁶ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁷ Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
⁷⁸ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
⁷⁹ Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸⁰ Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁸¹ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
⁸² Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁸³ Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁸⁴ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Ontario, Canada.
⁸⁵ Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.
⁸⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁸⁷ Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
⁸⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁹⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany University of Tübingen, Tübingen, Germany.
⁹¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
⁹² Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹³ Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
⁹⁴ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.

PMID: 26921362
PMCID: PMC4938802
DOI: 10.1136/jmedgenet-2015-103529

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Douglas F Easton et al. J Med Genet. 2016 May.

. 2016 May;53(5):298-309.

doi: 10.1136/jmedgenet-2015-103529. Epub 2016 Feb 26.

Authors

Affiliations

¹ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
² Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, Paris, France.
³ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Cancer Genetics and Comparative Genomics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁵ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁷ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁸ Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
⁹ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
¹⁰ Genetic of Breast Cancer Team, Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France.
¹¹ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹³ Department of Epidemiology, University of California Irvine, Irvine, California, USA.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
¹⁶ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
¹⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁸ International Epidemiology Institute, Rockville, Maryland, USA Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁰ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁴ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
²⁵ Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
²⁶ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
²⁹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles, California, USA.
³⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
³¹ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece.
³³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
³⁴ Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁵ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
³⁶ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
³⁷ University Paris-Sud, UMRS 1018, Villejuif, France Inserm, CESP Center for research in Epidemiology and Population Health, U1018, Cancer & Environment Group, Villejuif, France.
³⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
³⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore Department of Surgery, National University Health System, Singapore, Singapore.
⁴⁰ Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁴¹ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴² Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
⁴³ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁴⁴ Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴⁵ Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California, USA Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁴⁶ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁴⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁴⁸ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁹ Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University, Seoul, Korea.
⁵⁰ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
⁵¹ Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), Oslo, Norway.
⁵² Vesalius Research Center, VIB, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
⁵³ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁵⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁵⁵ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁵⁶ Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK.
⁵⁷ Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.
⁵⁸ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
⁵⁹ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁶⁰ Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
⁶¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁶² Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK Institute of Population Health, University of Manchester, Manchester, UK.
⁶³ University Hospital Gashuisberg, Leuven, Belgium.
⁶⁴ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁵ IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
⁶⁶ Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
⁶⁷ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁶⁸ Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
⁶⁹ National Cancer Institute, Bangkok, Thailand.
⁷⁰ Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany Medical Faculty, Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
⁷¹ School of Public Health, China Medical University, Taichung, Taiwan Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁷² Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁷³ Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁴ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁷⁶ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁷ Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
⁷⁸ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
⁷⁹ Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸⁰ Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁸¹ Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
⁸² Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁸³ Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁸⁴ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Ontario, Canada.
⁸⁵ Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.
⁸⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁸⁷ Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
⁸⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
⁹⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany University of Tübingen, Tübingen, Germany.
⁹¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
⁹² Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹³ Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
⁹⁴ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.

PMID: 26921362
PMCID: PMC4938802
DOI: 10.1136/jmedgenet-2015-103529

Abstract

Background: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.

Methods: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.

Results: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).

Conclusions: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Keywords: Cancer: breast.

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Conflict of interest statement

Competing interests

GM reports grants from Cancer Australia during the conduct of the study; personal fees from AstraZeneca outside the submitted work. AS reports grants from Breast Cancer Now (previously Breakthrough Breast Cancer) during the conduct of the study. SVT reports grants from US National Cancer Institute during the conduct of the study and is an inventor on most of the key BRCA1 and BRCA2 patents. The claims in these patents that constrained commercial genetic testing by entities other than Myriad Genetics have been overturned, expired or abandoned. MWB reports grants from ELAN Found during the conduct of the study. DEG has US Patent nos. 5747282; 5710001; 5837942; 6033857 with royalties paid by Myriad Genetics. CV reports grants from NCI during the conduct of the study. PAF reports grants and/or personal fees from Amgen, Novartis, Biomarin, Roche, Pfizer, GSK, TEVA and Genomic Health, outside the submitted work. RNL reports grants from Medical Research Council and Cancer Research UK during the conduct of the study.

Figures

**Figure 1**
Cluster plot for genotype intensities for rs137852986 on the iCOGS array. Normalised intensities for the variant and wild-type allele for each individual are given by the X and Y coordinates, respectively. Individuals called as p.Arg798Ter carriers are indicated by green dots and non-carriers by blue dots. The red dot indicates a positive control individual known to carry the variant from prior sequencing. BCAC, Breast Cancer Association Consortium; NC, no call.

**Figure 2**
Sequencing of cDNA from a cycloheximide-treated and untreated lymphoblastoid cell line from a *BRIP1* p.Arg798Ter carrier. Forward sequence of (A) cDNA from cycloheximide-treated lymphoblastoid cell line, (B) cDNA from the untreated lymphoblastoid cell line and (C) DNA sequence from the same cell line.

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Comment in

Risky business: getting a grip on BRIP.
Sopik V, Foulkes WD. Sopik V, et al. J Med Genet. 2016 May;53(5):296-7. doi: 10.1136/jmedgenet-2015-103648. Epub 2016 Feb 26. J Med Genet. 2016. PMID: 26921361 No abstract available.

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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

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