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 UNIMI - Università degli Studi di Milano = University of Milan
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 = Charité - University Hospital [Berlin]
24 Genetics
25 Department 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 et de Biologie Moléculaire [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 UC Santa Cruz - 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

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: uncertain significance; clinical; quantitative; variant; classification; BRCA1; BRCA2; multifactorial

Domains: Life Sciences [q-bio]; Human health and pathology

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, 2019, 40 (9), pp.1557-1578. ⟨10.1002/humu.23818⟩. ⟨hal-02194510⟩