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Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

2019; Wiley; Volume: 40; Issue: 9 Linguagem: Inglês

10.1002/humu.23818

1098-1004

Michael T. Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, Barbara Wappenschmidt, Lídia Feliubadaló, Cora M. Aalfs, Simona Agata, Kristiina Aittomäki, Elisa Alducci, María Concepción Alonso‐Cerezo, Norbert Arnold, Bernd Auber, Rachel Austin, Jacopo Azzollini, Judith Balmañà, Elena Barbieri, Claus R. Bartram, Ana Blanco, Britta Blümcke, Sandra Bonache, Bernardo Bonanni, Åke Borg, Beatrice Bortesi, Joan Brunet, Carla Bruzzone, Karolin Bucksch, Giulia Cagnoli, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Gabriele Lorenzo Capone, Sandrine M. Caputo, Ileana Carnevali, Estela Carrasco, Virginie Caux‐Moncoutier, Pietro Cavalli, Giulia Cini, Edward Clarke, Paola Concolino, Elisa J. Cops, Laura Cortesi, Fergus J. Couch, Esther Darder, Miguel de la Hoya, Michael Dean, Irmgard Debatin, Jesús Del Valle, Capucine Delnatte, Nicolas Derive, Orland Dı́ez, Nina Ditsch, Susan M. Domchek, Véronique Dutrannoy, Diana Eccles, Hans Ehrencrona, Ute Enders, D. Gareth Evans, Chantal Farra, Ulrike Faust, Ute Felbor, Irène Feroce, Miriam Fine, William D. Foulkes, Henrique C.R. Galvão, Gaetana Gambino, Andrea Gehrig, Francesca Gensini, Anne–Marie Gerdes, Aldo Germani, J Giesecke, Viviana Gismondi, Carolina Gómez, E. Gómez, Sara González, Èlia Grau, Sabine Grill, Eva Groß, Aliana Guerrieri‐Gonzaga, Marine Guillaud‐Bataille, Sara Gutiérrez‐Enríquez, Thomas Haaf, Karl Hackmann, Thomas van Overeem Hansen, Marion Harris, Jan Hauke, T. Heinrich, Heide Hellebrand, Karen Herold, Ellen Honisch, Judit Horváth, Claude Houdayer, Verena Hübbel, Sílvia Iglesias, À. Izquierdo, Paul A. James, Linda A.M. Janssen, Udo Jeschke, Silke Kaulfuß, Katharina Keupp, Marion Kiechle, Alexandra C. Kölbl, Sophie Krieger, Torben A. Kruse, Anders Kvist, Fiona Lalloo, Mirjam Larsen, Vanessa Lattimore, Charlotte Kvist Lautrup, Susanne Ledig, Elena Leinert, Alexandra Lewis, Joanna Lim, Markus Loeffler, Adrià López‐Fernández, Emanuela Lucci‐Cordisco, Nicolai Maass, Siranoush Manoukian, Monica Marabelli, Laura Matricardi, Alfons Meindl, Rodrigo D. Michelli, Setareh Moghadasi, Alejandro Moles‐Fernández, Marco Montagna, Gemma Montalban, Álvaro N.A. Monteiro, Eva Montes, Luigi Mori, Lidia Moserle, Clemens R. Müller, Christoph Mundhenke, Nadia Naldi, Katherine L. Nathanson, Matilde Navarro, Heli Nevanlinna, Cassandra Nichols, Dieter Niederacher, Henriette Roed Nielsen, Kai‐ren Ong, Nicholas Pachter, Edenir Inêz Palmero, Laura Papi, Inge Søkilde Pedersen, Bernard Peissel, Pedro Pérez‐Segura, Katharina Pfeifer, Marta Pineda, Esther Pohl‐Rescigno, Nicola Poplawski, Berardino Porfirio, Anne S. Quante, Juliane Ramser, Rui Manuel Reis, Françoise Révillion, Kerstin Rhiem, Barbara Riboli, Julia Ritter, Daniela Rivera, Paula Rofes, Andreas Rump, Mònica Salinas, A.M. SÁnchez De Abajo, Gunnar Schmidt, Ulrike Schoenwiese, Jochen Seggewiß, Ares Solanes, Doris Steinemann, Mathias Stiller, Dominique Stoppa‐Lyonnet, Kelly J. Sullivan, Rachel Susman, Christian Sutter, Sean V. Tavtigian, Soo‐Hwang Teo, Àlex Teulé, Mads Thomassen, Maria Grazia Tibiletti, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Eva Tornero, Therese Törngren, Sara Torres‐Esquius, Angela Toss, Alison H. Trainer, Kathy Tucker, Christi J. van Asperen, Marion van Mackelenbergh, Liliana Varesco, Gardenia Vargas‐Parra, Raymonda Varon, Ana Vega, Ángela Velasco, Anne‐Sophie Vesper, Alessandra Viel, Maaike P.G. Vreeswijk, Sebastian Wagner, Anke Waha, Logan C. Walker, Rhiannon Walters, Shan Wang‐Gohrke, Bernhard Weber, Wilko Weichert, Kerstin Wieland, Lisa Wiesmüller, Isabell Witzel, Achim Wöckel, Emma R. Woodward, Silke Zachariae, Valentina Zampiga, C Zeder-Göß, KConFab Investigators, Conxi Lázaro, Arcangela De Nicolo, Paolo Radice, Christoph Engel, Rita K. Schmutzler, David E. Goldgar, Amanda B. Spurdle,

Cancer Genomics and Diagnostics

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.