Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Funding Information: The authors gratefully thank all patients and their families for submitting their data and all the collaborators, researchers, clinicians, technicians and coordinating teams who have enabled this work to be carried out. We acknowledge the Cyprus Institute of Neurology and Genetics (CING), the CING institution and the Telethon organisation Cyprus for supporting this work. We acknowledge the contribution of the CIMBA (https://cimba.ccge.medschl.cam.ac.uk/) and ENIGMA (https://enigmaconsortium.org/) consortium, members and collaborators. We also acknowledge the contributions of the OTTA consortium (https://ottaconsortium.org/) and the AOCS Group (http://www.aocstudy.org). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Cancer Foundation. CIMBA acknowledges: All the families and clinicians who contributed to the studies; Catherine M. Phelan for her contribution to CIMBA until she passed away on 22 September 2017; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; clinicians, patients, researchers, technicians and nurses of A.C. Camargo Cancer Center for their contribution to this study; Oncogenetic Department, Clinical and Functional Genomics Group, Center of Genomic Diagnostics, Biobank and other International Research Center-CIPE’ facilities at AC. Camargo Cancer Center, especially Karina Miranda Santiago, Giovana Tardin Torrezan, José Claudio Casali, Nirvana Formiga and Fabiana Baroni Makdissi; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen for the recruitment and genetic counselling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; all the individuals and the researchers who took part in CONSIT TEAM (Consorzio Italiano Tumori Ereditari Alla Mammella), in particular: Dario Zimbalatti, Daniela Zaffaroni, Laura Ottini, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. The FCCC cohort (Godwin) acknowledges Ms. JoEllen Weaver and Dr. Betsy Bove, and the KUMC cohort (Sharma and Godwin) acknowledge the support of Michele Park, Lauren DiMartino, Alex Webster and the current and past members of the Biospecimen Repository Core Facility (BRCF) at KUMC; all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Muhammad U. Rashid, Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Diana Torres, Ignacio Briceno, Fabian Gil). FPGMX: members of the Cancer Genetics group (IDIS): Marta Santamariña, Miguel E. Aguado-Barrera, Olivia Fuentes Ríos and Ana Crujeiras-González; the GIIS025 research nurses and staff for their contributions to this resource, and the many families who contribute to GIIS025; IFE - Leipzig Research Centre for Civilisation Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber); Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the June 30, 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Génétique, Institut Curie, Paris, France: Muriel Belotti, Ophélie Bertrand, Anne-Marie Birot, Bruno Buecher, Sandrine Caputo, Chrystelle Colas, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Marine Le Mentec, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Dominique Stoppa-Lyonnet, and Inserm U900, Institut Curie, Paris, France: Fabienne Lesueur, Noura Mebirouk, Yue Jiao. Contributing Centres: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France: Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Mélanie Léone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, Odile Cabaret, Olivier Caron, Marine Guillaud-Bataille, Etienne Rouleau. Centre Jean Perrin, Clermont–Ferrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon, France: Valérie Bonadona, Sophie Dussart, Christine Lasset, Pauline Rochefort. Centre François Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Noguès, Tetsuro Noguchi, Cornel Popovici Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurélie Dumont, Françoise Révillion. Centre Paul Strauss, Strasbourg, France: Danièle Muller. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Anaïs Dupré, Anne Floquet, Michel Longy, Marie Louty, Cécile Maninna, Nicolas Sevenet, Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: Hélène Dreyfus, Dominique Leroux, Clémentine Legrand, Christine Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Laurence Faivre, Caroline Jacquot, Sarab Lizard, Sophie Nambot. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Véronique Mari. CHU Limoges, France: Laurence Vénat-Bouvet. CHU Nantes, France: Stéphane Bézieau, Capucine Delnatte. CHU Bretonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris, France: Florence Coulet, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besançon, France: Marie-Agnès Collonge-Rame. CHU Poitiers, Centre Hospitalier d’Angoulême and Centre Hospitalier de Niort, France: Stéphanie Chieze-Valero, Paul Gesta, Brigitte Gilbert-Dussardier. Centre Hospitalier de La Rochelle: Hakima Lallaoui. CHU Nîmes Carémeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; CHU de Martinique, France: Odile Bera; Mickaelle Rose; Drs. Taru A. Muranen and Carl Blomqvist, RN Outi Malkavaara; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centres: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, M.J. Hooning, I.A. Boere; I.R. Geurts-Giele; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez García, M.J. Blok, M. de Boer; University Medical Center Groningen, University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): Q.J.M Voorham; the study participants and the registration teams of IKNL and PALGA for part of the HEBON data collection; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Attila Patócs, János Papp, Anikó Bozsik, Timea Pócza, Henriett Butz, Zoltán Mátrai, Lajos Géczi, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; Fatemeh Yadegari, Shiva Zarinfam and Rezvan Esmaeili for their role in participant enrollment and biospecimen and data management; the study participants and registration teams of the Hereditary Cancer Genetics Group of the Valld’Hebron Institute of Oncolgy (VHIO) and the Clinical and Molecular Genetics Department of the University Hospital Vall d’Hebron (HVH), the Cellex Foundation for providing research facilities, and CERCA Programme/Generalitat de Catalunya for institutional support; members and participants of the Inherited Cancer Registry (ICARE); the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skilful assistance; Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; all participants and the collaborators from RCGEB “Georgi D. Efremov”, MASA (Ivana Maleva Kostovska, Simona Jakovcevska, Sanja Kiprijanovska), University Clinic of Radiotherapy and Oncology (Snezhana Smichkoska, Emilija Lazarova, Marina Iljovska), Adzibadem-Sistina Hospital (Katerina Kubelka-Sabit, Dzengis Jasar, Mitko Karadjozov), and Re-Medika Hospital (Andrej Arsovski and Liljana Stojanovska) for their contributions and commitment to the MACBRCA study; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); Petra Kleiblova, Marketa Janatova, Jana Soukupova (Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague (VFN), Czechia), Petra Zemankova, Petr Nehasil (Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, Czechia), Michal Vocka (Department of Oncology, General University Hospital in Prague (VFN), Czechia), Anne Lincoln, Lauren Jacobs; the participants in Hereditary Breast/Ovarian Cancer Study and Breast Imaging Study for their selfless contributions to our research; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the staff of Genetic Health Service NZ and the families who have contributed; members and participants in the Ontario Cancer Genetics Network; Hayley Cassingham. Leigha Senter, Kevin Sweet, Julia Cooper, and Amber Aielts; research nurses and staff of Breast Unit, Pauls Stradins Clinical University Hopsital, RSUIO and the many families who contribute to the CIMBA registry of RSUIO; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation, Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively; the National Cancer Centre Singapore Cancer Genetics Service (NCCS) for patient recruitement; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Simon Gayther and Patricia Harrington; Geoffrey Lindeman, Marion Harris, Joanne McKinley, Simone McInerny, and Ella Thompson for performing all DNA amplification. HEBCS thanks Drs. Kristiina Aittomäki, Carl Blomqvist and Taru A. Muranen and research nurses Irja Erkkilä and Outi Malkavaara. HJO acknowledges the oncologists Tjoung-Won Park-Simon and Peter Hillemanns at Hannover Medical School, Clemens Liebrich at the Gynecology Clinics Wolfsburg, Ingo Runnebaum at the Gynaecology Clinics at the University of Jena, and Peter Dall at the Gynecology Clinics at the University of Lüneburg for providing clinical data and medical records to this analysis, Peter Schürmann for technical assistance, and Dhanya Ramachandran for contributing to BRCA1 and BRCA2 VUS analyses. The contents of the published material are solely the responsibility of the authors and do not reflect the views of NHMRC. Publisher Copyright: © 2023, The Author(s).Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.Peer reviewe