Journal articles

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 [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 = 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 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 : uncertain significance clinical quantitative variant classification BRCA1 BRCA2 multifactorial

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Human health and pathology

Complete list of metadata

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Submitted on : Thursday, July 25, 2019 - 3:49:31 PM
Last modification on : Tuesday, April 12, 2022 - 3:19:15 AM