A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2

Maria Zanti¹, Denise G O'Mahony¹, Michael T Parsons², Hongyan Li³, Joe Dennis⁴, Kristiina Aittomäkkiki⁵, Irene L Andrulis^{6

7}, Hoda Anton-Culver⁸, Kristan J Aronson⁹, Annelie Augustinsson¹⁰, Heiko Becher¹¹, Stig E Bojesen^{12

13

14}, Manjeet K Bolla⁴, Hermann Brenner^{15

16

17}, Melissa A Brown¹⁸, Saundra S Buys¹⁹, Federico Canzian²⁰, Sandrine M Caputo^{21

22}, Jose E Castelao²³, Jenny Chang-Claude^{24

25}; GC-HBOC study Collaborators; Kamila Czene²⁶, Mary B Daly²⁷, Arcangela De Nicolo²⁸, Peter Devilee^{29

30}, Thilo Dörk³¹, Alison M Dunning³², Miriam Dwek³³, Diana M Eccles³⁴, Christoph Engel^{35

36}, D Gareth Evans^{37

38}, Peter A Fasching³⁹, Manuela Gago-Dominguez⁴⁰, Montserrat García-Closas⁴¹, José A García-Sáenz⁴², Aleksandra Gentry-Maharaj⁴³, Willemina R R Geurts-Giele⁴⁴, Graham G Giles^{45

46

47}, Gord Glendon⁶, Mark S Goldberg^{48

49}, Encarna B Gómez Garcia⁵⁰, Melanie Güendert^{51

52

53}, Pascal Guénel⁵⁴, Eric Hahnen^{55

56}, Christopher A Haiman⁵⁷, Per Hall^{26

58}, Ute Hamann⁵⁹, Elaine F Harkness^{60

61

62}, Frans B L Hogervorst⁶³, Antoinette Hollestelle⁶⁴, Reiner Hoppe^{65

66}, John L Hopper⁴⁶, Claude Houdayer⁶⁷, Richard S Houlston⁶⁸, Anthony Howell⁶⁹; ABCTB Investigators; Milena Jakimovska⁷⁰, Anna Jakubowska^{71

72}, Helena Jernström¹⁰, Esther M John^{73

74}, Rudolf Kaaks²⁴, Cari M Kitahara⁷⁵, Stella Koutros⁴¹, Peter Kraft^{76

77}, Vessela N Kristensen^{78

79}, James V Lacey^{80

81}, Diether Lambrechts^{82

83}, Melanie Léoné⁸⁴, Annika Lindblom^{85

86}, Jan Lubiński⁷¹, Michael Lush⁴, Arto Mannermaa^{87

88

89}, Mehdi Manoochehri⁵⁹, Siranoush Manoukian⁹⁰, Sara Margolin^{58

91}, Maria Elena Martinez^{92

93}, Usha Menon⁴³, Roger L Milne^{45

46

47}, Alvaro N Monteiro⁹⁴, Rachel A Murphy^{95

96}, Susan L Neuhausen⁹⁷, Heli Nevanlinna⁹⁸, William G Newman^{37

38}, Kenneth Offit^{99

100}, Sue K Park^{101

102

103}, Paul James^{104

105}, Paolo Peterlongo¹⁰⁶, Julian Peto¹⁰⁷, Dijana Plaseska-Karanfilska⁷⁰, Kevin Punie¹⁰⁸, Paolo Radice¹⁰⁹, Muhammad U Rashid^{59

110}, Gad Rennert¹¹¹, Atocha Romero¹¹², Efraim H Rosenberg¹¹³, Emmanouil Saloustros¹¹⁴, Dale P Sandler¹¹⁵, Marjanka K Schmidt^{116

117

118}, Rita K Schmutzler^{55

56

119}, Xiao-Ou Shu¹²⁰, Jacques Simard¹²¹, Melissa C Southey^{45

47

122}, Jennifer Stone^{46

123}, Dominique Stoppa-Lyonnet^{21

124

125}, Rulla M Tamimi^{77

126}, William J Tapper³⁴, Jack A Taylor^{115

127}, Soo Hwang Teo^{128

129}, Lauren R Teras¹³⁰, Mary Beth Terry¹³¹, Mads Thomassen¹³², Melissa A Troester¹³³, Celine M Vachon¹³⁴, Ana Vega^{135

136

137}, Maaike P G Vreeswijk³⁰, Qin Wang⁴, Barbara Wappenschmidt^{55

56}, Clarice R Weinberg¹³⁸, Alicja Wolk^{139

140}, Wei Zheng¹²⁰, Bingjian Feng¹⁴¹, Fergus J Couch¹⁴², Amanda B Spurdle², Douglas F Easton^{4

32}, David E Goldgar¹⁴¹, Kyriaki Michailidou^{1

4}

Affiliations

¹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
² Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³ Cancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁶ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁹ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁰ Oncology, Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.
¹¹ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹² Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹³ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁴ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
¹⁹ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²⁰ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Service de Génétique, Institut Curie, Paris, France.
²² Paris Sciences Lettres Research University, Paris, France.
²³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
²⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁷ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
²⁸ Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²⁹ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
³⁰ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³¹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³³ School of Life Sciences, University of Westminster, London, UK.
³⁴ Faculty of Medicine, University of Southampton, Southampton, UK.
³⁵ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³⁶ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
³⁷ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
³⁸ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
³⁹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴⁰ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁴¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁴² Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁴³ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁴⁴ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁷ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴⁸ Department of Medicine, McGill University, Montréal, QC, Canada.
⁴⁹ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁵⁰ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
⁵¹ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵² Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁵³ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁴ Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
⁵⁵ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁶ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁸ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁰ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁶¹ Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁶² NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁶³ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
⁶⁴ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁶⁵ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶⁶ University of Tübingen, Tübingen, Germany.
⁶⁷ Department of Genetics, F76000 and Normandy University, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France.
⁶⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁹ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁷⁰ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁷¹ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁷² Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁷³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁴ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁵ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁶ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁸ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷⁹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁸⁰ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁸¹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁸² Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁸³ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁸⁴ Genetic and Cancer Medical Laboratory HCL-CLB, Hospices Civils de Lyon, Bron, France.
⁸⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁸⁷ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁸⁸ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁸⁹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁹⁰ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
⁹¹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁹² Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁹³ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
⁹⁴ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁹⁵ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁹⁶ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁹⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁹⁸ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹⁹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁰ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰¹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
¹⁰² Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰³ Cancer Research Institute, Seoul National University, Seoul, Korea.
¹⁰⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁵ Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁰⁶ Genome Diagnostics Program, IFOM - ETS the AIRC Institute of Molecular Oncology, Milan, Italy.
¹⁰⁷ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁰⁸ Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute and University Hospitals Leuven, Leuven, Belgium.
¹⁰⁹ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹¹⁰ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹¹¹ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹¹² Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹¹³ Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
¹¹⁴ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹¹⁶ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹¹⁷ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
¹¹⁸ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
¹¹⁹ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹²¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹²² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹²³ Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.
¹²⁴ Department of Tumour Biology, INSERM U830, Paris, France.
¹²⁵ Université Paris Descartes, Paris, France.
¹²⁶ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹²⁷ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁸ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹²⁹ Department of Surgery, Faculty of Medicine, University of Malaya, UM Cancer Research Institute, Kuala Lumpur, Malaysia.
¹³⁰ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹³¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹³² Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
¹³³ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁴ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹³⁵ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹³⁶ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹³⁷ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹³⁸ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹³⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁴⁰ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴¹ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

PMID: 38725546
PMCID: PMC11080979
DOI: 10.1155/2023/9961341

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2

Maria Zanti et al. Hum Mutat. 2023.

. 2023:2023:9961341.

doi: 10.1155/2023/9961341. Epub 2023 Sep 14.

Authors

Affiliations

¹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
² Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³ Cancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁶ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁹ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁰ Oncology, Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.
¹¹ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹² Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹³ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁴ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁸ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
¹⁹ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²⁰ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Service de Génétique, Institut Curie, Paris, France.
²² Paris Sciences Lettres Research University, Paris, France.
²³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
²⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁷ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
²⁸ Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²⁹ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
³⁰ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³¹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³³ School of Life Sciences, University of Westminster, London, UK.
³⁴ Faculty of Medicine, University of Southampton, Southampton, UK.
³⁵ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³⁶ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
³⁷ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
³⁸ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
³⁹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴⁰ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁴¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁴² Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁴³ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁴⁴ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁷ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴⁸ Department of Medicine, McGill University, Montréal, QC, Canada.
⁴⁹ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁵⁰ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
⁵¹ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵² Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁵³ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁴ Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
⁵⁵ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁶ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁸ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁰ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁶¹ Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁶² NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁶³ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
⁶⁴ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁶⁵ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶⁶ University of Tübingen, Tübingen, Germany.
⁶⁷ Department of Genetics, F76000 and Normandy University, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France.
⁶⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁹ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁷⁰ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁷¹ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁷² Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁷³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁴ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁵ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁶ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁸ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷⁹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁸⁰ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁸¹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁸² Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁸³ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁸⁴ Genetic and Cancer Medical Laboratory HCL-CLB, Hospices Civils de Lyon, Bron, France.
⁸⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁸⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁸⁷ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁸⁸ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁸⁹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁹⁰ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
⁹¹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁹² Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁹³ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
⁹⁴ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁹⁵ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁹⁶ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁹⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁹⁸ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹⁹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁰ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰¹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
¹⁰² Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰³ Cancer Research Institute, Seoul National University, Seoul, Korea.
¹⁰⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁵ Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁰⁶ Genome Diagnostics Program, IFOM - ETS the AIRC Institute of Molecular Oncology, Milan, Italy.
¹⁰⁷ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁰⁸ Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute and University Hospitals Leuven, Leuven, Belgium.
¹⁰⁹ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹¹⁰ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹¹¹ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹¹² Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹¹³ Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
¹¹⁴ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹¹⁶ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹¹⁷ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands.
¹¹⁸ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
¹¹⁹ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹²¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹²² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹²³ Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.
¹²⁴ Department of Tumour Biology, INSERM U830, Paris, France.
¹²⁵ Université Paris Descartes, Paris, France.
¹²⁶ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹²⁷ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁸ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹²⁹ Department of Surgery, Faculty of Medicine, University of Malaya, UM Cancer Research Institute, Kuala Lumpur, Malaysia.
¹³⁰ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹³¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹³² Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
¹³³ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁴ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹³⁵ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹³⁶ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹³⁷ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹³⁸ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹³⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁴⁰ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴¹ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

PMID: 38725546
PMCID: PMC11080979
DOI: 10.1155/2023/9961341

Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Keywords: ACMG/AMP; BRCA; PS4; VUS; case-control; likelihood ratio; variant classification.

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Conflict of interest statement

The following authors declare conflicts not directly relevant to this work as stated below. Usha Menon has a patent (no: EP10178345.4) for Breast Cancer Diagnostics and held personal shares in Abcodia between 1st April 2011 and 30 October 2021. She is a member of the Research Advisory Panel, Yorkshire Cancer Research, Trial Steering Committee, NOVEL, and Scientific Advisory Board of Tina's Wish. She has received grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. She is part of research collaborations with iLOF, RNG Guardian and Micronoma. All other authors declare that they have no conflict of interests.

Figures

**Figure 1**
Performance of the case-control likelihood ratio method and odds ratio analysis in providing at least strong ACMG/AMP evidence in favor of pathogenicity (LR ≥ 18.7) using simulated datasets. Power equals the probability of reaching at least strong pathogenic ACMG/AMP evidence. Genotype data simulations were carried out for causal variants conferring disease relative risk between 2 and 10. We performed 10,000 simulations for each case scenario. Results represent simulated case-control data for 20,000 (a–c), 30,000 (d–f), or 50,000 (g–i) breast cancer cases and controls and minor allele frequency of 0.00003 (a, d, g), 0.00005 (b, e, h), or 0.0001 (c, f, i). ccLR: case-control likelihood ratio; MAF: minor allele frequency; N: sample size.

**Figure 2**
Performance of the case-control likelihood ratio method in providing ACMG/AMP evidence against pathogenicity, using simulated datasets. Power equals to the probability of reaching at least supporting benign ACMG/AMP evidence (LR ≤0.48) when the relative risk was set to 1. We performed 10,000 simulations for each case scenario. Results represent simulated case-control data for 20,000, 30,000, or 50,000 breast cancer cases and controls and minor allele frequency of 0.00003, 0.00005, or 0.0001. ccLR: case-control likelihood ratio; MAF: minor allele frequency; N: sample size.

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References

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A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2

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A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2

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