Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
Parsons Michael T, Tudini Emma, Li Hongyan, Hahnen Eric, Wappenschmidt Barbara, Feliubadaló Lidia, Aalfs Cora M, Agata Simona, Aittomäki Kristiina, Alducci Elisa, Alonso-Cerezo María Concepción, Arnold Norbert, Auber Bernd, Austin Rachel, Azzollini Jacopo, Balmaña Judith, Barbieri Elena, Bartram Claus R, Blanco Ana, Blümcke Britta, Bonache Sandra, Bonanni Bernardo, Borg Åke, Bortesi Beatrice, Brunet Joan, Bruzzone Carla, Bucksch Karolin, Cagnoli Giulia, Caldés Trinidad, Caliebe Almuth, Caligo Maria A, Calvello Mariarosaria, Capone Gabriele L, Caputo Sandrine M, Carnevali Ileana, Carrasco Estela, Caux-Moncoutier Virginie, Cavalli Pietro, Cini Giulia, Clarke Edward M, Concolino Paola, Cops Elisa J, Cortesi Laura, Couch Fergus J, Darder Esther, de la Hoya Miguel, Dean Michael, Debatin Irmgard, Del Valle Jesús, Delnatte Capucine, Derive Nicolas, Diez Orland, Ditsch Nina, Domchek Susan M, Dutrannoy Véronique, Eccles Diana M, Ehrencrona Hans, Enders Ute, Evans D Gareth, Farra Chantal, Faust Ulrike, Felbor Ute, Feroce Irene, Fine Miriam, Foulkes William D, Galvao Henrique C R, Gambino Gaetana, Gehrig Andrea, Gensini Francesca, Gerdes Anne-Marie, Germani Aldo, Giesecke Jutta, Gismondi Viviana, Gómez Carolina, Gómez Garcia Encarna B, González Sara, Grau Elia, Grill Sabine, Gross Eva, Guerrieri-Gonzaga Aliana, Guillaud-Bataille Marine, Gutiérrez-Enríquez Sara, Haaf Thomas, Hackmann Karl, Hansen Thomas V O, Harris Marion, Hauke Jan, Heinrich Tilman, Hellebrand Heide, Herold Karen N, Honisch Ellen, Horvath Judit, Houdayer Claude, Hübbel Verena, Iglesias Silvia, Izquierdo Angel, James Paul A, Janssen Linda A M, Jeschke Udo, Kaulfuß Silke, Keupp Katharina, Kiechle Marion, Kölbl Alexandra, Krieger Sophie, Kruse Torben A, Kvist Anders, Lalloo Fiona, Larsen Mirjam, Lattimore Vanessa L, Lautrup Charlotte, Ledig Susanne, Leinert Elena, Lewis Alexandra L, Lim Joanna, Loeffler Markus, López-Fernández Adrià, Lucci-Cordisco Emanuela, Maass Nicolai, Manoukian Siranoush, Marabelli Monica, Matricardi Laura, Meindl Alfons, Michelli Rodrigo D, Moghadasi Setareh, Moles-Fernández Alejandro, Montagna Marco, Montalban Gemma, Monteiro Alvaro N, Montes Eva, Mori Luigi, Moserle Lidia, Müller Clemens R, Mundhenke Christoph, Naldi Nadia, Nathanson Katherine L, Navarro Matilde, Nevanlinna Heli, Nichols Cassandra B, Niederacher Dieter, Nielsen Henriette R, Ong Kai-Ren, Pachter Nicholas, Palmero Edenir I, Papi Laura, Pedersen Inge Sokilde, Peissel Bernard, Perez-Segura Pedro, Pfeifer Katharina, Pineda Marta, Pohl-Rescigno Esther, Poplawski Nicola K, Porfirio Berardino, Quante Anne S, Ramser Juliane, Reis Rui M, Revillion Françoise, Rhiem Kerstin, Riboli Barbara, Ritter Julia, Rivera Daniela, Rofes Paula, Rump Andreas, Salinas Monica, Sánchez de Abajo Ana María, Schmidt Gunnar, Schoenwiese Ulrike, Seggewiß Jochen, Solanes Ares, Steinemann Doris, Stiller Mathias, Stoppa-Lyonnet Dominique, Sullivan Kelly J, Susman Rachel, Sutter Christian, Tavtigian Sean V, Teo Soo H, Teulé Alex, Thomassen Mads, Tibiletti Maria Grazia, Tischkowitz Marc, Tognazzo Silvia, Toland Amanda E, Tornero Eva, Törngren Therese, Torres-Esquius Sara, Toss Angela, Trainer Alison H, Tucker Katherine M, van Asperen Christi J, van Mackelenbergh Marion T, Varesco Liliana, Vargas-Parra Gardenia, Varon Raymonda, Vega Ana, Velasco Ángela, Vesper Anne-Sophie, Viel Alessandra, Vreeswijk Maaike P G, Wagner Sebastian A, Waha Anke, Walker Logan C, Walters Rhiannon J, Wang-Gohrke Shan, Weber Bernhard H F, Weichert Wilko, Wieland Kerstin, Wiesmüller Lisa, Witzel Isabell, Wöckel Achim, Woodward Emma R, Zachariae Silke, Zampiga Valentina, Zeder-Göß Christine, KConFab Investigators, Lázaro Conxi, De Nicolo Arcangela, Radice Paolo, Engel Christoph, Schmutzler Rita K, Goldgar David E, Spurdle Amanda B
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Аннотация
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.
Для цитирования: Parsons Michael T, Tudini Emma, Li Hongyan, Hahnen Eric, Wappenschmidt Barbara, Feliubadaló Lidia, Aalfs Cora M, Agata Simona, Aittomäki Kristiina, Alducci Elisa, Alonso-Cerezo María Concepción, Arnold Norbert, Auber Bernd, Austin Rachel, Azzollini Jacopo, Balmaña Judith, Barbieri Elena, Bartram Claus R, Blanco Ana, Blümcke Britta, Bonache Sandra, Bonanni Bernardo, Borg Åke, Bortesi Beatrice, Brunet Joan, Bruzzone Carla, Bucksch Karolin, Cagnoli Giulia, Caldés Trinidad, Caliebe Almuth, Caligo Maria A, Calvello Mariarosaria, Capone Gabriele L, Caputo Sandrine M, Carnevali Ileana, Carrasco Estela, Caux-Moncoutier Virginie, Cavalli Pietro, Cini Giulia, Clarke Edward M, Concolino Paola, Cops Elisa J, Cortesi Laura, Couch Fergus J, Darder Esther, de la Hoya Miguel, Dean Michael, Debatin Irmgard, Del Valle Jesús, Delnatte Capucine, Derive Nicolas, Diez Orland, Ditsch Nina, Domchek Susan M, Dutrannoy Véronique, Eccles Diana M, Ehrencrona Hans, Enders Ute, Evans D Gareth, Farra Chantal, Faust Ulrike, Felbor Ute, Feroce Irene, Fine Miriam, Foulkes William D, Galvao Henrique C R, Gambino Gaetana, Gehrig Andrea, Gensini Francesca, Gerdes Anne-Marie, Germani Aldo, Giesecke Jutta, Gismondi Viviana, Gómez Carolina, Gómez Garcia Encarna B, González Sara, Grau Elia, Grill Sabine, Gross Eva, Guerrieri-Gonzaga Aliana, Guillaud-Bataille Marine, Gutiérrez-Enríquez Sara, Haaf Thomas, Hackmann Karl, Hansen Thomas V O, Harris Marion, Hauke Jan, Heinrich Tilman, Hellebrand Heide, Herold Karen N, Honisch Ellen, Horvath Judit, Houdayer Claude, Hübbel Verena, Iglesias Silvia, Izquierdo Angel, James Paul A, Janssen Linda A M, Jeschke Udo, Kaulfuß Silke, Keupp Katharina, Kiechle Marion, Kölbl Alexandra, Krieger Sophie, Kruse Torben A, Kvist Anders, Lalloo Fiona, Larsen Mirjam, Lattimore Vanessa L, Lautrup Charlotte, Ledig Susanne, Leinert Elena, Lewis Alexandra L, Lim Joanna, Loeffler Markus, López-Fernández Adrià, Lucci-Cordisco Emanuela, Maass Nicolai, Manoukian Siranoush, Marabelli Monica, Matricardi Laura, Meindl Alfons, Michelli Rodrigo D, Moghadasi Setareh, Moles-Fernández Alejandro, Montagna Marco, Montalban Gemma, Monteiro Alvaro N, Montes Eva, Mori Luigi, Moserle Lidia, Müller Clemens R, Mundhenke Christoph, Naldi Nadia, Nathanson Katherine L, Navarro Matilde, Nevanlinna Heli, Nichols Cassandra B, Niederacher Dieter, Nielsen Henriette R, Ong Kai-Ren, Pachter Nicholas, Palmero Edenir I, Papi Laura, Pedersen Inge Sokilde, Peissel Bernard, Perez-Segura Pedro, Pfeifer Katharina, Pineda Marta, Pohl-Rescigno Esther, Poplawski Nicola K, Porfirio Berardino, Quante Anne S, Ramser Juliane, Reis Rui M, Revillion Françoise, Rhiem Kerstin, Riboli Barbara, Ritter Julia, Rivera Daniela, Rofes Paula, Rump Andreas, Salinas Monica, Sánchez de Abajo Ana María, Schmidt Gunnar, Schoenwiese Ulrike, Seggewiß Jochen, Solanes Ares, Steinemann Doris, Stiller Mathias, Stoppa-Lyonnet Dominique, Sullivan Kelly J, Susman Rachel, Sutter Christian, Tavtigian Sean V, Teo Soo H, Teulé Alex, Thomassen Mads, Tibiletti Maria Grazia, Tischkowitz Marc, Tognazzo Silvia, Toland Amanda E, Tornero Eva, Törngren Therese, Torres-Esquius Sara, Toss Angela, Trainer Alison H, Tucker Katherine M, van Asperen Christi J, van Mackelenbergh Marion T, Varesco Liliana, Vargas-Parra Gardenia, Varon Raymonda, Vega Ana, Velasco Ángela, Vesper Anne-Sophie, Viel Alessandra, Vreeswijk Maaike P G, Wagner Sebastian A, Waha Anke, Walker Logan C, Walters Rhiannon J, Wang-Gohrke Shan, Weber Bernhard H F, Weichert Wilko, Wieland Kerstin, Wiesmüller Lisa, Witzel Isabell, Wöckel Achim, Woodward Emma R, Zachariae Silke, Zampiga Valentina, Zeder-Göß Christine, KConFab Investigators, Lázaro Conxi, De Nicolo Arcangela, Radice Paolo, Engel Christoph, Schmutzler Rita K, Goldgar David E, Spurdle Amanda B. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.. Human mutation. 2019. DOI: 10.1002/humu.23818.
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