Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2
Denise G O'Mahony, Susan J. Ramus, Melissa C. Southey, Nicola S. Meagher, Andreas Hadjisavvas, Esther M. John, Ute Hamann, Evgeny N. Imyanitov, Irene L. Andrulis, Priyanka Sharma, Mary B. Daly, Christopher R. Hake, Jeffrey N. Weitzel, Anna Jakubowska, Andrew K. Godwin, Aðalgeir Arason, Anita Bane, Jacques Simard, Penny Soucy, Maria A. Caligo, Phuong L. Mai, Kathleen Claes, Manuel R. Teixeira, Wendy K. Chung, Conxi Lázaro, Peter J. Hulick, Amanda E. Toland, Inge Søkilde Pedersen, HEBON Investigators, Marian J.E. Mourits, Susan L. Neuhausen, Ana Vega, Miguel de la Hoya, Heli Nevanlinna, Mallika Dhawan, Valentina Zampiga, Rita Danesi, Liliana Varesco, Viviana Gismondi, Valerio Gaetano Vellone, Paul A. James, Ramūnas Janavičius, Liene Ņikitina-Zaķe, Finn Cilius Nielsen, Thomas van Overeem Hansen, Tanja Pejović, Åke Borg, Johanna Rantala, Kenneth Offit, Marco Montagna, Katherine L. Nathanson, Susan M. Domchek, Ana Osório, María J. García, Beth Y. Karlan, GEMO Study Collaborators, Fabienne Lesueur, Anna de Fazio, David D.L. Bowtell, AOCS Group, Anna de Fazio, Lesley McGuffog, Goska Leslie, Michael T. Parsons, Thilo Dörk, Lisa‐Marie Speith, Elizabeth Santana Dos Santos, Alexandre André Balieiro Anastácio da Costa, Paolo Radice, Paolo Peterlongo, Laura Papi, Christoph Engel, Eric Hahnen, Rita K. Schmutzler, Barbara Wappenschmidt, Douglas F. Easton, Marc Tischkowitz, Christian F. Singer, Yen Y. Tan, Alice S. Whittemore, Weiva Sieh, James D. Brenton, Drakoulis Yannoukakos, Florentia Fostira, Irene Konstantopoulou, Jana Soukupová, Michal Vočka, Georgia Chenevix‐Trench, Paul D.P. Pharoah, Antonis C. Antoniou, David E. Goldgar, Amanda B. Spurdle, Kyriaki Michailidou, Miguel de la Hoya, Thomas van Overeem Hansen, Elizabeth Santana Dos Santos
Abstract
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ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.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.