Parsons, Michael T. and Tudini, Emma and Li, Hongyan and Hahnen, Eric and Wappenschmidt, Barbara and Feliubadalo, Lidia and Aalfs, Cora M. and Agata, Simona and Aittomaki, Kristiina and Alducci, Elisa and Concepcion Alonso-Cerezo, Maria and Arnold, Norbert and Auber, Bernd and Austin, Rachel and Azzollini, Jacopo and Balmana, Judith and Barbieri, Elena and Bartram, Claus R. and Blanco, Ana and Bluemcke, Britta and Bonache, Sandra and Bonanni, Bernardo and Borg, Ake and Bortesi, Beatrice and Brunet, Joan and Bruzzone, Carla and Bucksch, Karolin and Cagnoli, Giulia and Caldes, Trinidad and Caliebe, Almuth and Caligo, Maria A. and Calvello, Mariarosaria and Capone, Gabriele L. and Caputo, Sandrine M. and Carnevali, Ileana and Carrasco, Estela and Caux-Moncoutier, Virginie and Cavalli, Pietro and Cini, Giulia and Clarke, Edward M. and Concolino, Paola and Cops, Elisa J. and Cortesi, Laura and Couch, Fergus J. and Darder, Esther and de la Hoya, Miguel and Dean, Michael and Debatin, Irmgard and Del Valle, Jesus and Delnatte, Capucine and Derive, Nicolas and Diez, Orland and Ditsch, Nina and Domchek, Susan M. and Dutrannoy, Veronique and Eccles, Diana M. and Ehrencrona, Hans and Enders, Ute and Evans, D. Gareth and Farra, Chantal and Faust, Ulrike and Felbor, Ute and Feroce, Irene and Fine, Miriam and Foulkes, William D. and Galvao, Henrique Cr and Gambino, Gaetana and Gehrig, Andrea and Gensini, Francesca and Gerdes, Anne-Marie and Germani, Aldo and Giesecke, Jutta and Gismondi, Viviana and Gomez, Carolina and Garcia, Encarna B. Gomez and Gonzalez, Sara and Grau, Elia and Grill, Sabine and Gross, Eva and Guerrieri-Gonzaga, Aliana and Guillaud-Bataille, Marine and Gutierrez-Enriquez, Sara and Haaf, Thomas and Hackmann, Karl and Hansen, Thomas Vo and Harris, Marion and Hauke, Jan and Heinrich, Tilman and Hellebrand, Heide and Herold, Karen N. and Honisch, Ellen and Horvath, Judit and Houdayer, Claude and Huebbel, Verena and Iglesias, Silvia and Izquierdo, Angel and James, Paul A. and Janssen, Linda Am and Jeschke, Udo and Kaulfuss, Silke and Keupp, Katharina and Kiechle, Marion and Koelbl, Alexandra and Krieger, Sophie and Kruse, Torben A. and Kvist, Anders and Lalloo, Fiona and Larsen, Mirjam and Lattimore, Vanessa L. and Lautrup, Charlotte and Ledig, Susanne and Leinert, Elena and Lewis, Alexandra L. and Lim, Joanna and Loeffler, Markus and Lopez-Fernandez, Adria and Lucci-Cordisco, Emanuela and Maass, Nicolai and Manoukian, Siranoush and Marabelli, Monica and Matricardi, Laura and Meindl, Alfons and Michelli, Rodrigo D. and Moghadasi, Setareh and Moles-Fernandez, Alejandro and Montagna, Marco and Montalban, Gemma and Monteiro, Alvaro N. and Montes, Eva and Mori, Luigi and Moserle, Lidia and Mueller, Clemens R. and Mundhenke, Christoph and Naldi, Nadia and Nathanson, Katherine L. and Navarro, Matilde and Nevanlinna, Heli and Nichols, Cassandra B. and Niederacher, Dieter and Nielsen, Henriette R. and Ong, Kai-ren and Pachter, Nicholas and Palmero, Edenir and Papi, Laura and Pedersen, Inge Sokilde and Peissel, Bernard and Perez-Segura, Pedro and Pfeifer, Katharina and Pineda, Marta and Pohl-Rescigno, Esther and Poplawski, Nicola K. and Porfirio, Berardino and Quante, Anne S. and Ramser, Juliane and Reis, Rui M. and Revillion, Francoise and Rhiem, Kerstin and Riboli, Barbara and Ritter, Julia and Rivera, Daniela and Rofes, Paula and Rump, Andreas and Salinas, Monica and Sanchez de Abajo, Ana Maria and Schmidt, Gunnar and Schoenwiese, Ulrike and Seggewiss, Jochen and Solanes, Ares and Steinemann, Doris and Stiller, Mathias and Stoppa-Lyonnet, Dominique and Sullivan, Kelly J. and Susman, Rachel and Sutter, Christian and Tavtigian, Sean and Teo, Soo H. and Teule, Alex and Thomassen, Mads and Tibiletti, Maria Grazia and Tischkowitz, Marc and Tognazzo, Silvia and Toland, Amanda E. and Tornero, Eva and Torngren, Therese and Torres-Esquius, Sara and Toss, Angela and Trainer, Alison H. and Tucker, Katherine M. and van Asperen, Christi J. and van Mackelenbergh, Marion T. and Varesco, Liliana and Vargas-Parra, Gardenia and Varon, Raymonda and Vega, Ana and Velasco, Angela and Vesper, Anne-Sophie and Viel, Alessandra and Vreeswijk, Maaike P. G. and Wagner, Sebastian A. and Waha, Anke and Walker, Logan C. and Walters, Rhiannon J. and Wang-Gohrke, Shan and Weber, Bernhard H. F. and Weichert, Wilko and Wieland, Kerstin and Wiesmueller, Lisa and Witzel, Isabell and Woeckel, Achim and Woodward, Emma R. and Zachariae, Silke and Zampiga, Valentina and Zeder-Goss, Christine and Lazaro, Conxi and De Nicolo, Arcangela and Radice, Paolo and Engel, Christoph and Schmutzler, Rita K. and Goldgar, David E. and Spurdle, Amanda B. (2019) Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. HUMAN MUTATION, 40 (9). pp. 1557-1578. ISSN 1059-7794, 1098-1004
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SEQUENCE VARIANTS; BREAST-CANCER; UNCERTAIN SIGNIFICANCE; INTEGRATED EVALUATION; FUNCTIONAL ASSAYS; SPLICING ANALYSIS; GUIDELINES; CLINGEN; OVARIAN; RISKS; BRCA1; BRCA2; classification; clinical; multifactorial; quantitative; uncertain significance; variant |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2020 05:14 |
| Last Modified: | 31 Mar 2020 05:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26325 |
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