Title: | Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification |
Author: | Parsons, Michael T. Tudini, Emma Li, Hongyan Hahnen, Eric Wappenschmidt, Barbara Feliubadaló i Elorza, Maria Lídia Aalfs, Cora M. Agata, Simona Aittomäki, Kristiina Alducci, Elisa Alonso Cerezo, María Concepción Hauke, Jan Heinrich, Tilman Törngren, Therese Hellebrand, Heide Arnold, Norbert Seggewiß, Jochen Caldés, Trinidad Herold, Karen N. Honisch, Ellen Naldi, Nadia Witzel, Isabell Walters, Rhiannon J. Rump, Andreas Horvath, Judit Poplawski, Nicola K. Velasco, Àngela Houdayer, Claude Brunet, Joan Cini, Giulia Hübbel, Verena Iglesias, Silvia Wöckel, Achim Steinemann, Doris Izquierdo, Angel Barbieri, Elena Wang Gohrke, Shan James, Paul A. Carnevali, Ileana Torres Esquius, Sara Janssen, Linda A.M. Jeschke, Udo Kruse, Torben A. Kölbl, Alexandra Ledig, Susanne Cops, Elisa J. Vesper, Anne Sophie Kaulfuß, Silke Porfirio, Berardino Auber, Bernd Weber, Bernhard H. F. Leinert, Elena Rofes, Paula Bruzzone, Carla Woodward, Emma R. Matricardi, Laura Solanes, Ares Carrasco, Estela Mackelenbergh, Marion T. Waha, Anke Nathanson, Katherine L. Tucker, Katherine M. Bucksch, Karolin Navarro, Matilde Faust, Ulrike Bonanni, Bernardo González, Sara Nevanlinna, Heli Nichols, Cassandra B. Cortesi, Laura Wiesmüller, Lisa Niederacher, Dieter Vreeswijk, Maaike P. G. Caux Moncoutier, Virginie Nielsen, Henriette R. Giesecke, Jutta Hackmann, Karl Azzollini, Jacopo Ong, Kai Ren Pachter, Nicholas Galvao, Henrique C.R. Couch, Fergus J. Palmero, Edenir I. Guerrieri Gonzaga, Aliana Cagnoli, Giulia Papi, Laura Asperen, Christi J. Pohl Rescigno, Esther Ramser, Juliane Cavalli, Pietro Pedersen, Inge Søkilde Wagner, Sebastian A. Felbor, Ute Darder, Esther Reis, Rui M. Wieland, Kerstin Gismondi, Viviana Blümcke, Britta Zachariae, Silke Calvello, Mariarosaria Stiller, Mathias Bartram, Claus R. Feroce, Irene Stoppa Lyonnet, Dominique Keupp, Katharina Hoya, Miguel Lucci Cordisco, Emanuela Sullivan, Kelly J. Susman, Rachel Zampiga, Valentina Guillaud Bataille, Marine Concolino, Paola Sutter, Christian Caliebe, Almuth Gómez, Carolina Tavtigian, Sean V. Lewis, Alexandra L. Montagna, Marco Teo, Soo H. Teulé, Alex Debatin, Irmgard Thomassen, Mads Kvist, Anders Gutiérrez Enríquez, Sara Tibiletti, Maria Grazia Meindl, Alfons Fine, Miriam Tischkowitz, Marc Blanco, Ana Toss, Angela Varesco, Liliana Montes, Eva Garcia, Encarna B. Tognazzo, Silvia Caligo, Maria A. Kiechle, Marion Haaf, Thomas Vargas Parra, Gardenía María Clarke, Edward M. Lim, Joanna Bonache, Sandra Dean, Michael Michelli, Rodrigo D. Gensini, Francesca Gross, Eva Zeder Göß, Christine Gambino, Gaetana Loeffler, Markus Investigators, Kconfab Peissel, Bernard Rivera, Daniela Lázaro García, Conxi Nicolo, Arcangela Mori, Luigi Harris, Marion Radice, Paolo Grau Garcés, Èlia Moghadasi, Setareh Engel, Christoph Revillion, Françoise Krieger, Sophie Schmutzler, Rita K. Goldgar, David E. Balmaña, Judith Austin, Rachel Borg, Åke Salinas, Monica López Fernández, Adrià Spurdle, Amanda B. Gehrig, Andrea Capone, Gabriele L. Moles Fernández, Alejandro Bortesi, Beatrice Grill, Sabine Pérez Segura, Pedro Moserle, Lidia Caputo, Sandrine M. Hansen, Thomas V.O. Rhiem, Kerstin Lattimore, Vanessa L. Marabelli, Monica Del Valle, Jesús Lalloo, Fiona Pfeifer, Katharina Delnatte, Capucine Toland, Amanda E. Müller, Clemens R. Viel, Alessandra Derive, Nicolas Diez, Orland Sánchez de Abajo, Ana María Monteiro, Alvaro N. Ditsch, Nina Maass, Nicolai Riboli, Barbara Domchek, Susan M. Varon-Mateeva, Raymonda Weichert, Wilko Dutrannoy, Véronique Eccles, Diana Ehrencrona, Hans Trainer, Alison H. Schmidt, Gunnar Enders, Ute Walker, Logan C. Pineda Riu, Marta Evans, D. Gareth Larsen, Mirjam Foulkes, William D. Gerdes, Anne Marie Ritter, Julia Farra, Chantal Manoukian, Siranoush Tornero, Eva Schoenwiese, Ulrike Germani, Aldo Montalban, Gemma Vega, Ana Lautrup, Charlotte Mundhenke, Christoph Quante, Anne S. |
Keywords: | Proteïnes Genètica Tumors Proteins Genetics Tumors |
Issue Date: | 1-Sep-2019 |
Publisher: | Wiley |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1002/humu.23818 |
It is part of: | Human Mutation, 2019, vol. 40, issue. 9, p. 1557-1578 |
URI: | http://hdl.handle.net/2445/174791 |
Related resource: | https://doi.org/10.1002/humu.23818 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
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