Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2
Authors: O’Mahony Denise G. , Ramus Susan J. , Southey Melissa C. , Meagher Nicola S. , Hadjisavvas Andreas , John Esther M. , Hamann Ute , Imyanitov Evgeny N. , Andrulis Irene L. , Sharma Priyanka , Daly Mary B. , Hake Christopher R. , Weitzel Jeffrey N. , Jakubowska Anna , Godwin Andrew K. , Arason Adalgeir , Bane Anita , Simard Jacques , Soucy Penny , Caligo Maria A. , Mai Phuong L. , Claes Kathleen B. M. , Teixeira Manuel R. , Chung Wendy K. , Lazaro Conxi , Hulick Peter J. , Toland Amanda E. , Pedersen Inge Sokilde ,   HEBON Investigators, Mourits Marian J. E. , Neuhausen Susan L. , Vega Ana , de la Hoya Miguel , Nevanlinna Heli , Dhawan Mallika , Zampiga Valentina , Danesi Rita , Varesco Liliana , Gismondi Viviana , Vellone Valerio Gaetano , James Paul A. , Janavicius Ramunas , Nikitina-Zake Liene , Nielsen Finn Cilius , van Overeem Hansen Thomas , Pejovic Tanja , Borg Ake , Rantala Johanna , Offit Kenneth , Montagna Marco , Nathanson Katherine L. , Domchek Susan M. , Osorio Ana , García María J. , Karlan Beth Y. ,   GEMO Study Collaborators, Lesueur Fabienne , De Fazio Anna , Bowtell David ,   AOCS Group, De Fazio Anna , McGuffog Lesley , Leslie Goska , Parsons Michael T. , Dörk Thilo , Speith Lisa-Marie , dos Santos Elizabeth Santana , da Costa Alexandre André B. A. , Radice Paolo , Peterlongo Paolo , Papi Laura , Engel Christoph , Hahnen Eric , Schmutzler Rita K. , Wappenschmidt Barbara , Easton Douglas F. , Tischkowitz Marc , Singer Christian F. , Tan Yen Yen , Whittemore Alice S. , Sieh Weiva , Brenton James D. , Yannoukakos Drakoulis , Fostira Florentia , Konstantopoulou Irene , Soukupova Jana , Vocka Michal ,   CZECANCA Consortium, Chenevix-Trench Georgia , Pharoah Paul D. P. , Antoniou Antonis C. , Goldgar David E. , Spurdle Amanda B. , Michailidou Kyriaki ,   The Consortium of Investigators of Modifiers of BRCA1/2, de la Hoya Miguel , van Overeem Hansen Thomas , dos Santos Elizabeth Santana ,   Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium
Published: April 2023

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.