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    Human mutation. 2018 Feb 15. doi: 10.1002/humu.23406
    Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations.
    Rebbeck TR1,  Friebel TM2,  Friedman E3,  Hamann U4,  Huo D5,  Kwong A6,  Olah E7,  Olopade OI8,  Solano AR9,  Teo SH10,  Thomassen M11,  Weitzel JN12,  Chan TL13,  Couch FJ14,  Goldgar DE15,  Kruse TA16,  Palmero EI17,  Park SK18,  Torres D19,  van Rensburg EJ20,  McGuffog L21,  Parsons MT22,  Leslie G23,  Aalfs CM24,  Abugattas J25,  Adlard J26,  Agata S27,  Aittomäki K28,  Andrews L29,  Andrulis IL30,  Arason A31,  Arnold N32,  Arun BK33,  Asseryanis E34,  Auerbach L35,  Azzollini J36,  Balmaña J37,  Barile M38,  Barkardottir RB39,  Barrowdale D40,  Benitez J41,  Berger A42,  Berger R43,  Blanco AM44,  Blazer KR45,  Blok MJ46,  Bonadona V47,  Bonanni B48,  Bradbury AR49,  Brewer C50,  Buecher B51,  Buys SS52,  Caldes T53,  Caliebe A54,  Caligo MA55,  Campbell I56,  Caputo S57,  Chiquette J58,  Chung WK59,  Claes KBM60,  Collée JM61,  Cook J62,  Davidson R63,  de la Hoya M64,  De Leeneer K65,  de Pauw A66,  Delnatte C67,  Diez O68,  Ding YC69,  Ditsch N70,  Domchek SM71,  Dorfling CM72,  Velazquez C73,  Dworniczak B74,  Eason J75,  Easton DF76,  Eeles R77,  Ehrencrona H78,  Ejlertsen B79,  Engel C80,  Engert S81,  Evans DG82,  Faivre L83,  Feliubadaló L84,  Ferrer SF85,  Foretova L86,  Fowler J87,  Frost D88,  Galvão HCR89,  Ganz PA90,  Garber J91,  Gauthier-Villars M92,  Gehrig A93,  Gerdes AM94,  Gesta P95,  Giannini G96,  Giraud S97,  Glendon G98,  Godwin AK99,  Greene MH100,  Gronwald J101,  Gutierrez-Barrera A102,  Hahnen E103,  Hauke J104,  Henderson A105,  Hentschel J106,  Hogervorst FBL107,  Honisch E108,  Imyanitov EN109,  Isaacs C110,  Izatt L111,  Izquierdo A112,  Jakubowska A113,  James P114,  Janavicius R115,  Jensen UB116,  John EM117,  Joseph V118,  Kaczmarek K119,  Karlan BY120,  Kast K121,  Investigators K122,  Kim SW123,  Konstantopoulou I124,  Korach J125,  Laitman Y126,  Lasa A127,  Lasset C128,  Lázaro C129,  Lee A130,  Lee MH131,  Lester J132,  Lesueur F133,  Liljegren A134,  Lindor NM135,  Longy M136,  Loud JT137,  Lu KH138,  Lubinski J139,  Machackova E140,  Manoukian S141,  Mari V142,  Martínez-Bouzas C143,  Matrai Z144,  Mebirouk N145,  Meijers-Heijboer HEJ146,  Meindl A147,  Mensenkamp AR148,  Mickys U149,  Miller A150,  Montagna M151,  Moysich KB152,  Mulligan AM153,  Musinsky J154,  Neuhausen SL155,  Nevanlinna H156,  Ngeow J157,  Nguyen HP158,  Niederacher D159,  Nielsen HR160,  Nielsen FC161,  Nussbaum RL162,  Offit K163,  Öfverholm A164,  Ong KR165,  Osorio A166,  Papi L167,  Papp J168,  Pasini B169,  Pedersen IS170,  MSc AP171,  MSc NP172,  Peterlongo P173,  Pohl E174,  Ba NP175,  Prajzendanc K176,  Prieur F177,  Pujol P178,  Radice P179,  Ramus SJ180,  Rantala J181,  Rashid MU182,  Rhiem K183,  Robson M184,  Rodriguez GC185,  Rogers MT186,  Rudaitis V187,  Schmidt AY188,  Schmutzler RK189,  Senter L190,  Shah PD191,  Sharma P192,  Side LE193,  Simard J194,  Singer CF195,  Skytte AB196,  Slavin TP197,  Snape K198,  Sobol H199,  Southey M200,  Steele L201,  Steinemann D202,  Sukiennicki G203,  Sutter C204,  Szabo CI205,  Tan YY206,  Teixeira MR207,  Terry MB208,  Teulé A209,  Thomas A210,  Thull DL211,  Tischkowitz M212,  Tognazzo S213,  Toland AE214,  Topka S215,  Trainer AH216,  Tung N217,  van Asperen CJ218,  van der Hout AH219,  van der Kolk LE220,  van der Luijt RB221,  Van Heetvelde M222,  Varesco L223,  Varon-Mateeva R224,  Vega A225,  Villarreal-Garza C226,  von Wachenfeldt A227,  Walker L228,  Wang-Gohrke S229,  Wappenschmidt B230,  Weber BHF231,  Yannoukakos D232,  Yoon SY233,  Zanzottera C234,  Zidan J235,  Zorn KK236,  Selkirk CGH237,  Hulick PJ238,  Chenevix-Trench G239,  Spurdle AB240,  Antoniou AC241,  Nathanson KL242
    Author information
    1Harvard TH Chan School of Public Health and Dana Farber Cancer Institute,  1101 Dana Building, 450 Brookline Ave,  Boston, MA, 02215, USA.
    2Harvard TH Chan School of Public Health and Dana Farber Cancer Institute,  1101 Dana Building, 450 Brookline Ave,  Boston, MA, 02215, USA.
    3The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    4Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
    55841 South Maryland Avenue, MC 2115 Chicago, IL, USA.
    6The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.
    7Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    85841 South Maryland Avenue, MC 2115 Chicago, IL, USA.
    9INBIOMED, Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry, Medical Direction, Buenos Aires, Paraguay 2155, C1121ABG, Argentina.
    10Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500, Malaysia.
    11Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
    12Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA.
    13Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium & Hospital, 1/F Li Shu Fan Block, 2 Village Road, Happy Valley, Hong Kong.
    14Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, USA.
    15Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT, 84132, USA.
    16Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
    17Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
    18Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Korea.
    19Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
    20Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa.
    21Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    22Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD 4006, Australia.
    23Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    24Department of Clinical Genetics, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
    25City of Hope Clinical Cancer Genomics Community Research Network, 1500 East Duarte Road, Duarte, CA, 91010, USA.
    26Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
    27Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata 64, Padua, Italy.
    28Department of Clinical Genetics, Helsinki University Hospital, P.O. BOX 160 (Meilahdentie 2), 00029 HUS, Finland.
    29Hereditary Cancer Clinic, Prince of Wales Hospital, High Street, Randwick, NSW 2031, Australia.
    30Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1 × 5, Canada.
    31Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland.
    32Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Germany.
    33Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX, USA.
    34Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.
    35Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.
    36Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy.
    37Department of Medical Oncology, University Hospital, Vall d'Hebron, Barcelona, Spain.
    38Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), via Ripamonti 435, 20141, Milan, Italy.
    39Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland.
    40Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    41Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    42Dept of OB/GYN, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, 1090 Vienna, Austria.
    43The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
    44UCSF Cancer Genetics and Prevention Program, San Francisco, CA, 94143-1714.
    45Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA.
    46Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
    47Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
    48Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), via Ripamonti 435, 20141, Milan, Italy.
    49Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    50Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
    51Service de Génétique, Institut Curie, 26, rue d'Ulm, Paris Cedex 05, France.
    52Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
    53Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, CIBERONC. Martin Lagos s/n, Madrid, Spain.
    54Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Germany.
    55Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
    56Research Division, Peter MacCallum Cancer Centre, 305 Gratten Street, Melbourne, VIC 3000, Australia.
    57Service de Génétique, Institut Curie, 26, rue d'Ulm, Paris Cedex 05, France.
    58CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, Canada.
    59Departments of Pediatrics and Medicine, 1150 St. Nicholas Avenue, Columbia University, New York, NY, 10032, USA.
    60Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Gent, Belgium.
    61Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
    62Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
    63Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK.
    64Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, CIBERONC. Martin Lagos s/n, Madrid, Spain.
    65Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Gent, Belgium.
    66Service de Génétique, Institut Curie, 26, rue d'Ulm, Paris Cedex 05, France.
    67Unité d'oncogénétique, ICO-Centre René Gauducheau, Boulevard Jacques Monod, 44805 Nantes Saint Herblain Cedex, France.
    68Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, Barcelona, Spain.
    69Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    70Department of Gynaecology and Obstetrics, Ludwig-Maximilian University Munich, Germany.
    71Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    72Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa.
    73Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM, Universidad de Valladolid, Centro Superior de Investigaciones Científicas, UVA-CSIC, Valladolid, Spain.
    74Institute of Human Genetics, University of Münster, Münster, Germany.
    75Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
    76Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    77Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK.
    78Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    79Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
    80Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
    81Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany.
    82Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
    83Centre de Lutte Contre le Cancer Georges François Leclerc, 1 rue Professeur Marion, BP 77 980, Dijon Cedex, France and Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France.
    84Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute), CIBERONC, Gran Via de l'Hospitalet, 199-203. 08908 L'Hospitalet, Barcelona, Spain.
    85Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, BP 1125 Chambéry, France.
    86Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic.
    87Ohio State University /Columbus Cancer Council, Columbus, OH, 43221, USA.
    88Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    89Oncogenetics Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
    90UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA, 90095-6900, USA.
    91Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
    92Service de Génétique, Institut Curie, 26, rue d'Ulm, Paris Cedex 05, France.
    93Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany.
    94Department of Clinical Genetics, Rigshospitalet 4062, Blegdamsvej 9, København Ø, Denmark.
    95Service Régional Oncogénétique Poitou-Charentes, Centre Hospitalier, 79021, Niort.
    96Department of Molecular Medicine, University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti, viale Regina Elena 291, 00161 Rome, Italy.
    97Bâtiment Cheney D, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
    98Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1 × 5, Canada.
    99Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard,4019 Wahl Hall East, MS 3040, University of Kansas Medical Center, Kansas City, Kansas, USA.
    100Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA.
    101Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    102Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX, USA.
    103Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
    104Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
    105Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
    106Institute of Human Genetics, University Leipzig, 04107 Leipzig, Germany.
    107Family Cancer Clinic, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands.
    108Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Germany.
    109N.N. Petrov Institute of Oncology, St.-Petersburg, 197758, Russia.
    110Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, USA.
    111Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
    112Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, CIBERONC, Av. França s/n, 1707, Girona, Spain.
    113Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    114Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, 305 Gratten Street, Melbourne, VIC 3000, Australia.
    115Vilnius University Hospital Santariskiu Clinics, Hereditary Cancer Competence Center Hematology, Oncology and Transfusion Medicine Center Room P519 Santariskiu st. 2, LT-08661, Vilnius, Lithuania.
    116Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21C, Aarhus N, Denmark.
    117Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA, 94538, USA.
    118Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    119Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    120Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA.
    121Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
    122Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Australia.
    123Department of Surgery, Daerim St. Mary's Hospital, 657 Siheung-daero, Yeongdeungpo-gu, Seoul, Korea.
    124Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research "Demokritos",, Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi Attikis, Athens, Greece.
    125The Gyneco-Oncology Department, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel.
    126The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
    127Servicio de Genética-CIBERER U705, Hospital de la Santa Creu i Sant Pau, Barcelona.
    128Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
    129Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute), CIBERONC, Gran Via de l'Hospitalet, 199-203. 08908 L'Hospitalet, Barcelona, Spain.
    130The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY.
    131Department of Surgery, Soonchunhyang University and Seoul Hospital, 59 Daesagwan-Ro, Yongsan-Gu, Seoul, Korea.
    132Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA.
    133Institut Curie, PSL Research University, Mines ParisTech, Inserm U900, 26 rue d'Ulm, F-75005, Paris, France.
    134Department of Oncology Radiumhemmet and Institution of Oncology and Patology, Karolinska University Hospital and Karolinska Institutet.
    135Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ, USA.
    136Oncogénétique, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux, France.
    137Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-536, Bethesda, MD, USA.
    138Department of Gynecological Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CPB 6, Houston, TX, USA.
    139Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    140Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic.
    141Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy.
    142Centre Antoine Lacassagne, 33 Avenue de Valombrose, Nice, France.
    143Laboratorio de Genética Molecular, Servicio de Genética, Hospital Universitario Cruces, BioCruces Health Research Institute, Spain.
    144Department of Surgery, National Institute of Oncology, Budapest, Hungary.
    145Institut Curie, PSL Research University, Mines ParisTech, Inserm U900, 26 rue d'Ulm, F-75005, Paris, France.
    146Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
    147Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany.
    148Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
    149Vilnius university Santariskiu hospital, National Center of Pathology, Baublio st. 5, Vilnius, Lithuania.
    150NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY, 14263, USA.
    151Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata 64, Padua, Italy.
    152Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
    153Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
    154Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    155Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    156Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700 (Haartmaninkatu 8), 00029 HUS, Finland.
    157Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610.
    158Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Germany.
    159Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Germany.
    160Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
    161Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Denmark.
    162513 Parnassus Ave., HSE 901E, San Francisco, CA, 94143 - 0794, USA.
    163Clinical Genetics Research Laboratory, Dept. of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    164Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    165West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK.
    166Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Spain. Biomedical Network on Rare Diseases (CIBERER), Madrid, Madrid, Spain.
    167Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
    168Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    169Department of Medical Sciences, University of Turin, Via Santena 19, 10126, Turin, Italy.
    170Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Reberbansgade 15, Aalborg, Denmark.
    171Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
    172Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    173IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, via Adamello 16, 20139, Milan, Italy.
    174Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
    175Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    176Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    177Service de Génétique Clinique Chromosomique et Moléculaire, Hôpital Nord, CHU Saint Etienne, St Etienne cedex 2, France.
    178Unité d'Oncogénétique, CHU Arnaud de Villeneuve, 34295, Montpellier Cedex 5, France.
    179Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133, Milan, Italy.
    180School of Women's and Children's Health, UNSW Sydney,  Australia.
    181Department of Clinical Genetics, Karolinska University Hospital L5:03, Stockholm, S-171 76, Sweden.
    182Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
    183Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
    184Clinical Genetics Services, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
    185Division of Gynecologic Oncology, North Shore University Health System, Clinical Professor, University of Chicago, 2650 Ridge Avenue, Suite 1507 Walgreens, Evanston, IL, 60201, USA.
    186All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
    187Vilnius University Hospital Santariskiu Clinics, Centre of Woman's Health and pathology, Department of Gynecology, Santariskiu st. 2, Vilnius, Lithuania.
    188Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Denmark.
    189Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
    190Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
    191Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    192Department of Hematology and Oncology, University of Kansas Medical Center, Suite 210, 2330 Shawnee Mission Parkway, Westwood, KS, USA.
    193North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
    194Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec, Canada.
    195Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, A 1090 Vienna, Austria.
    196Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21C, Aarhus N, Denmark.
    197Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA.
    198Medical Genetics Unit, St George's, University of London, UK.
    199Département Oncologie Génétique, Prévention et Dépistage, Institut Paoli-Calmettes, 232 boulevard Sainte-Margueritte, Marseille, France.
    200Département Oncologie Génétique, Prévention et Dépistage, Institut Paoli-Calmettes, 232 boulevard Sainte-Margueritte, Marseille, France.
    201Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    202Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
    203Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    204Department of Human Genetics, University Hospital Heidelberg, Germany.
    205National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD, USA.
    206Dept of OB/GYN, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, Waehringer Guertel 18-20, 1090 Vienna, Austria.
    207Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
    208Department of Epidemiology, Columbia University, New York, NY, USA.
    209Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Gran Via de l'Hospitalet, 199-203. 08908 L'Hospitalet, Barcelona, Spain.
    210Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, USA.
    211Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    212Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada.
    213Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata 64, Padua, Italy.
    214Division of Human Genetics, Departments of Internal Medicine and Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, 460 W. 12th Avenue, Columbus, OH, USA.
    215Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    216Parkville Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia.
    217Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue Boston, Massachusetts, 02215, USA.
    218Department of Clinical Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
    219Department of Genetics, University Medical Center Groningen, University Groningen, The Netherlands.
    220Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    221Department of Medical Genetics, University Medical Center Utrecht, The Netherlands.
    222Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Gent, Belgium.
    223Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, largo Rosanna Benzi 10, 16132, Genoa, Italy.
    224Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany.
    225Fundación Pública Galega Medicina Xenómica, calle Choupana s/n, Edificio de Consultas, Planta menos dos Santiago de Compostal, A Coruña, Spain.
    226Departamento de Investigacion y de Tumores Mamarios del Instituto Nacional de Cancerologia, Mexico City.
    227Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    228Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK.
    229Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany.
    230Department of Genetics and Pathology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, Poland.
    231Institute of Human Genetics, University Regensburg, Germany.
    232Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research "Demokritos",, Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi Attikis, Athens, Greece.
    233Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500, Malaysia.
    234Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy.
    235Institute of Oncology, Rivka Ziv Medical Center, 13000, Zefat, Israel.
    236Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    237Center for Medical Genetics, NorthShore University HealthSystem, 1000 Central St, Suite 620, Evanston, IL, USA.
    238Medical Director, Center for Medical Genetics, North Shore University Health System, Clinical Assistant Professor of Medicine, University of Chicago Pritzker School of Medicine, 1000 Central Street, Suite 620, Evanston, IL, 60201, USA.
    239Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD 4006, Australia.
    240Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD 4006, Australia.
    241Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    242Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    Abstract

    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on 6 continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. This article is protected by copyright. All rights reserved.


    This article is protected by copyright. All rights reserved.

    KEYWORDS: BRCA1, BRCA2, breast cancer, ethnicity, geography, mutation, ovarian cancer

    Publikations ID: 29446198
    Quelle: öffnen
     
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