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

Françoise Revillion Michael T. Parsons 1 Emma Tudini Hongyan Li 2 Eric Hahnen Barbara Wappenschmidt 3 Lídia Feliubadaló 4 Cora M. Aalfs 5 Simona Agata Kristiina Aittomäki 6 Elisa Alducci María Concepción Alonso‐cerezo Norbert Arnold 7 Bernd Auber Rachel Austin Jacopo Azzollini 8 Judith Balmaña 9 Elena Barbieri Claus R. Bartram 10 Ana Blanco 11 Britta Blümcke Sandra Bonache Bernardo Bonanni 12 Åke Borg 13 Beatrice Bortesi Joan Brunet 14 Carla Bruzzone Karolin Bucksch Giulia Cagnoli Trinidad Caldes 15 Almuth Caliebe Maria A. Caligo Mariarosaria Calvello Gabriele L. Capone Sandrine M. Caputo 16 Ileana Carnevali Estela Carrasco Virginie Caux‐moncoutier Pietro Cavalli Giulia Cini Edward M. Clarke Paola Concolino Elisa J. Cops Laura Cortesi Fergus J. Couch Esther Darder 17 Miguel de La Hoya 18 Michael Dean Irmgard Debatin Jesús Del Valle Capucine Delnatte 19 Nicolas Derive 20 Orland Diez 21 Nina Ditsch 22 Susan M. Domchek Véronique Dutrannoy 23 Diana M. Eccles 24 Hans Ehrencrona 25 Ute Enders D. Gareth Evans 26 Ulrike Faust Ute Felbor Irene Feroce Miriam Fine Henrique C.R. Galvao Gaetana Gambino Andrea Gehrig 27 Francesca Gensini Anne‐marie Gerdes Aldo Germani Jutta Giesecke Viviana Gismondi Carolina Gomez Encarna B. Gómez Garcia Sara Gonzalez 28 Elia Grau Sabine Grill Eva Gross 29 Aliana Guerrieri‐gonzaga Marine Guillaud‐bataille Sara Gutiérrez‐enríquez Thomas Haaf 30 Karl Hackmann Thomas V.O. Hansen Marion Harris Jan Hauke Tilman Heinrich Heide Hellebrand 29 Karen N. Herold Ellen Honisch 31 Judit Horvath 32 Claude Houdayer 33 Verena Hübbel Silvia Iglesias Angel Izquierdo Paul A. James Linda A.M. Janssen Udo Jeschke 34 Silke Kaulfuß Katharina Keupp Marion Kiechle 29 Alexandra Kölbl Sophie Krieger 35, 36 Torben A. Kruse 37 Anders Kvist 38 Fiona Lalloo 39 Mirjam Larsen Vanessa L. Lattimore Charlotte Lautrup Susanne Ledig Elena Leinert Alexandra L. Lewis Joanna Lim Markus Loeffler 40 Adrià López‐fernández Emanuela Lucci‐cordisco Nicolai Maass 41 Siranoush Manoukian 42 Monica Marabelli Laura Matricardi Alfons Meindl 43 Rodrigo D. Michelli Setareh Moghadasi Alejandro Moles‐fernández Marco Montagna 44 Gemma Montalban Alvaro N. Monteiro Eva Montes Luigi Mori Lidia Moserle Clemens R. Müller Christoph Mundhenke 45 Nadia Naldi Katherine L. Nathanson Matilde Navarro Heli Nevanlinna 46 Cassandra B. Nichols Dieter Niederacher 47 Henriette R. Nielsen Kai‐ren Ong Nicholas Pachter Edenir I. Palmero Laura Papi 48 Inge Søkilde Pedersen 49 Bernard Peissel 42 Pedro Pérez‐segura Katharina Pfeifer Marta Pineda Esther Pohl‐rescigno Nicola K. Poplawski Berardino Porfirio Anne S. Quante Juliane Ramser Rui M. Reis Françoise Révillion 50 Kerstin Rhiem 51 Barbara Riboli Julia Ritter Daniela Rivera Paula Rofes Andreas Rump Monica Salinas Ana María Sánchez De Abajo Gunnar Schmidt Ulrike Schoenwiese Jochen Seggewiß Ares Solanes Doris Steinemann 52 Mathias Stiller 53 Dominique Stoppa‐lyonnet Kelly J. Sullivan Rachel Susman Christian Sutter 54 Sean V. Tavtigian 55 Soo H. Teo Alex Teulé 56 Mads Thomassen 57 Maria Grazia Tibiletti Silvia Tognazzo 58 Amanda E. Toland Eva Tornero 59 Therese Törngren Sara Torres‐esquius Angela Toss Alison H. Trainer Christi J. Van Asperen Marion T. Van Mackelenbergh Liliana Varesco 60 Gardenia Vargas‐parra Raymonda Varon 61 Ana Vega 62 Ángela Velasco Anne‐sophie Vesper Alessandra Viel 63 Maaike P.G. Vreeswijk Sebastian A. Wagner Anke Waha Logan C. Walker 64 Rhiannon J. Walters Shan Wang‐gohrke Bernhard H.F. Weber Wilko Weichert 65 Kerstin Wieland Lisa Wiesmüller Isabell Witzel 66 Achim Wöckel Emma R. Woodward Silke Zachariae Valentina Zampiga Christine Zeder‐göß Kconfab Investigators 67 Conxi Lazaro 68 Arcangela De Nicolo Paolo Radice 69 Christoph Engel 70 Rita K. Schmutzler 71 David E. Goldgar Amanda B. Spurdle 1
1 QIMR Berghofer Medical Research Institute
2 CAGS - Chinese Academy of Geological Sciences [Beijing]
3 Department of Gynaecology and Obstetrics
4 Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional
5 Department of Clinical Genetics
6 Department of Clinical Genetics
7 Department of Gynaecology and Obstetrics
8 Università degli studi di Milano [Milano]
9 Medical Oncology Department
10 Institute of Human Genetics
11 Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC
12 Division of Cancer Prevention and Genetics
13 Department of Oncology, Clinical Sciences
14 Genetic Counseling and Hereditary Cancer Programme
15 Molecular Oncology Laboratory
16 Institut Curie [Paris]
17 Programa de Consell Genètic en Càncer, Institut Català d'Oncologia
18 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
19 Centre René Gauducheau
20 IBGC - Institut de biochimie et génétique cellulaires
21 Oncogenetics Laboratory
22 Department of Gynaecology and Obstetrics
23 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin
24 Genetics
25 Departament of Genetics and Pathology
26 Department of Genomic Medicine
27 Department of Medical Genetics
28 Catalan Institute of Oncology
29 Obstetrics and Gynaecology
30 Institüt für Humangenetik [Würzburg]
31 Obstetrics and Gynaecology
32 Institute of Chemistry [Budapest]
33 Service de biochimie [CHU Trousseau]
34 I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet
35 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
36 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
37 Department of Biochemistry, Pharmacology and Genetics
38 Department of Oncology
39 Genetic Medicine
40 Institute for Medical Informatics
41 Department of Gynecology and Obstetrics
42 Unit of Medical Genetics
43 Department of Gynaecology and Obstetrics
44 Immunology and Molecular Oncology Unit
45 Department of Gynecology and Obstetrics
46 Department of Obstetrics and Gynecology
47 Department of Gynaecology and Obstetrics
48 Medical Genetics Unit
49 Department of Biochemistry, Section of Molecular Diagnostics
50 Laboratoire d'Oncologie Moléculaire Humaine
51 Department of Gynaecology and Obstetrics
52 Institute of Cell and Molecular Pathology
53 UCSC - University of California [Santa Cruz]
54 Institute of Human Genetics
55 IACR - International Agency for Cancer Research
56 Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL
57 Department of Clinical Genetics
58 Immunology and Molecular Oncology Unit
59 Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals
60 Unit of Hereditary Cancers
61 Institute of Human Genetics
62 CIBER de Enfermedades Raras (CIBERER)
63 Unit of Experimental Oncology 1
64 University of Otago [Dunedin, Nouvelle-Zélande]
65 Institute of Pathology
66 Department of Gynecology
67 King‘s College London
68 Molecular Diagnostic Unit
69 Unit of Molecular Bases of Genetic Risk and Genetic Testing
70 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
71 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics
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.
Keywords : multifactorial variant classification BRCA1 BRCA2 uncertain significance clinical quantitative
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Journal articles
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02194510
Contributor : Université Normandie <>
Submitted on : Thursday, July 25, 2019 - 3:49:31 PM
Last modification on : Wednesday, October 14, 2020 - 4:15:06 AM

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COMUE-NORMANDIE | CURIE | BACLESSE | LAMBRET | ICO | GAUDUCHEAU | CNRS | FNCLCC | UNIROUEN | GPMCND | PSL

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Françoise Revillion, Michael T. Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, et al.. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Human Mutation, Wiley, 2019, 40 (9), pp.1557-1578. ⟨10.1002/humu.23818⟩. ⟨hal-02194510⟩

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