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

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Parsons , M T , Tudini , E , Li , H , Hahnen , E , Wappenschmidt , B , Feliubadaló , L , Aalfs , C M , Agata , S , Aittomäki , K , Alducci , E , Alonso-Cerezo , M C , Arnold , N , Auber , B , Austin , R , Azzollini , J , Balmaña , J , Barbieri , E , Bartram , C R , Blanco , A , Blümcke , B , Bonache , S , Bonanni , B , Borg , Å , Bortesi , B , Brunet , J , Bruzzone , C , Bucksch , K , Cagnoli , G , Caldés , T , Caliebe , A , Caligo , M A , Calvello , M , Capone , G L , Caputo , S M , Carnevali , I , Carrasco , E , Caux-Moncoutier , V , Cavalli , P , Cini , G , Clarke , E M , Concolino , P , Cops , E J , Cortesi , L , Couch , F J , Darder , E , de la Hoya , M , Dean , M , Debatin , I , del Valle , J , Delnatte , C , Derive , N , Diez , O , Ditsch , N , Domchek , S M , Dutrannoy , V , Eccles , D M , Ehrencrona , H , Enders , U , Evans , D G , Faust , U , Felbor , U , Feroce , I , Fine , M , Galvao , H C R , Gambino , G , Gehrig , A , Gensini , F , Gerdes , A-M , Germani , A , Giesecke , J , Gismondi , V , Gómez , C , Gómez Garcia , E B , González , S , Grau , E , Grill , S , Gross , E , Guerrieri-Gonzaga , A , Guillaud-Bataille , M , Gutiérrez-Enríquez , S , Haaf , T , Hackmann , K , Hansen , T V O , Harris , M , Hauke , J , Heinrich , T , Hellebrand , H , Herold , K N , Honisch , E , Horvath , J , Houdayer , C , Hübbel , V , Iglesias , S , Izquierdo , A , James , P A , Janssen , L A M , Jeschke , U , Kaulfuß , S , Keupp , K , Kiechle , M , Kölbl , A , Krieger , S , Kruse , T A , Kvist , A , Lalloo , F , Larsen , M , Lattimore , V L , Lautrup , C , Ledig , S , Leinert , E , Lewis , A L , Lim , J , Loeffler , M , López-Fernández , A , Lucci-Cordisco , E , Maass , N , Manoukian , S , Marabelli , M , Matricardi , L , Meindl , A , Michelli , R D , Moghadasi , S , Moles-Fernández , A , Montagna , M , Montalban , G , Monteiro , A N , Montes , E , Mori , L , Moserle , L , Müller , C R , Mundhenke , C , Naldi , N , Nathanson , K L , Navarro , M , Nevanlinna , H , Nichols , C B , Niederacher , D , Nielsen , H R , Ong , K , Pachter , N , Palmero , E I , Papi , L , Pedersen , I S , Peissel , B , Pérez-Segura , P , Pfeifer , K , Pineda , M , Pohl-Rescigno , E , Poplawski , N K , Porfirio , B , Quante , A S , Ramser , J , Reis , R M , Revillion , F , Rhiem , K , Riboli , B , Ritter , J , Rivera , D , Rofes , P , Rump , A , Salinas , M , Sánchez de Abajo , A M , Schmidt , G , Schoenwiese , U , Seggewiß , J , Solanes , A , Steinemann , D , Stiller , M , Stoppa-Lyonnet , D , Sullivan , K J , Susman , R , Sutter , C , Tavtigian , S V , Teo , S H , Teulé , A , Thomassen , M , Tibiletti , M G , Tognazzo , S , Toland , A E , Tornero , E , Törngren , T , Torres-Esquius , S , Toss , A , Trainer , A H , van Asperen , C J , van Mackelenbergh , M T , Varesco , L , Vargas-Parra , G , Varon , R , Vega , A , Velasco , Á , Vesper , A-S , Viel , A , Vreeswijk , M P G , Wagner , S A , Waha , A , Walker , L C , Walters , R J , Wang-Gohrke , S , Weber , B H F , Weichert , W , Wieland , K , Wiesmüller , L , Witzel , I , Wöckel , A , Woodward , E R , Zachariae , S , Zampiga , V , Zeder-Göß , C , Investigators , KC , Lázaro , C , De Nicolo , A , Radice , P , Engel , C , Schmutzler , R K , Goldgar , D E & Spurdle , A B 2019 , ' Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification ' , Human Mutation , vol. 40 , no. 9 , pp. 1557-1578 . https://doi.org/10.1002/humu.23818

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, 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; Faust, Ulrike; Felbor, Ute; Feroce, Irene; Fine, Miriam; 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; Pérez-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; Tognazzo, Silvia; Toland, Amanda E.; Tornero, Eva; Törngren, Therese; Torres-Esquius, Sara; Toss, Angela; Trainer, Alison H.; 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; Investigators, KConFab; Lázaro, Conxi; De Nicolo, Arcangela; Radice, Paolo; Engel, Christoph; Schmutzler, Rita K.; Goldgar, David E.; Spurdle, Amanda B.
Contributor: University of Helsinki, Medicum
University of Helsinki, HUS Gynecology and Obstetrics
Date: 2019-09
Language: eng
Number of pages: 22
Belongs to series: Human Mutation
ISSN: 1059-7794
URI: http://hdl.handle.net/10138/306576
Abstract: 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 1395 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; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to 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 non-pathogenic 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. This article is protected by copyright. All rights reserved.
Subject: 1184 Genetics, developmental biology, physiology
BRCA1
BRCA2
quantitative
clinical
classification
multifactorial
variant
uncertain significance
RISKS
GUIDELINES
SEQUENCE VARIANTS
SPLICING ANALYSIS
INTEGRATED EVALUATION
BREAST-CANCER
FUNCTIONAL ASSAYS
CLINGEN
OVARIAN
UNCERTAIN SIGNIFICANCE
3111 Biomedicine
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