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. 2019 Sep;40(9):1557-1578.
doi: 10.1002/humu.23818.

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

Michael T Parsons  1 , Emma Tudini  1 , Hongyan Li  2 , Eric Hahnen  3   4 , Barbara Wappenschmidt  3   4 , Lidia Feliubadaló  5 , Cora M Aalfs  6 , Simona Agata  7 , Kristiina Aittomäki  8 , Elisa Alducci  7 , María Concepción Alonso-Cerezo  9 , Norbert Arnold  10   11 , Bernd Auber  12 , Rachel Austin  13 , Jacopo Azzollini  14 , Judith Balmaña  15   16 , Elena Barbieri  17 , Claus R Bartram  18 , Ana Blanco  19 , Britta Blümcke  3   4 , Sandra Bonache  20 , Bernardo Bonanni  21 , Åke Borg  22 , Beatrice Bortesi  23 , Joan Brunet  5 , Carla Bruzzone  24 , Karolin Bucksch  25 , Giulia Cagnoli  14 , Trinidad Caldés  26 , Almuth Caliebe  27 , Maria A Caligo  28 , Mariarosaria Calvello  21 , Gabriele L Capone  29 , Sandrine M Caputo  30   31 , Ileana Carnevali  32 , Estela Carrasco  15 , Virginie Caux-Moncoutier  30 , Pietro Cavalli  33 , Giulia Cini  34 , Edward M Clarke  1 , Paola Concolino  35 , Elisa J Cops  36 , Laura Cortesi  17 , Fergus J Couch  37 , Esther Darder  5 , Miguel de la Hoya  26 , Michael Dean  38 , Irmgard Debatin  39 , Jesús Del Valle  5 , Capucine Delnatte  40 , Nicolas Derive  30   31 , Orland Diez  20   41 , Nina Ditsch  42 , Susan M Domchek  43 , Véronique Dutrannoy  44 , Diana M Eccles  45 , Hans Ehrencrona  46   47 , Ute Enders  25 , D Gareth Evans  48   49 , Chantal Farra  50 , Ulrike Faust  51 , Ute Felbor  52 , Irene Feroce  21 , Miriam Fine  53 , William D Foulkes  54 , Henrique C R Galvao  55 , Gaetana Gambino  28 , Andrea Gehrig  56 , Francesca Gensini  29 , Anne-Marie Gerdes  57 , Aldo Germani  58 , Jutta Giesecke  3   4 , Viviana Gismondi  24 , Carolina Gómez  5 , Encarna B Gómez Garcia  59 , Sara González  5 , Elia Grau  5 , Sabine Grill  60 , Eva Gross  42 , Aliana Guerrieri-Gonzaga  21 , Marine Guillaud-Bataille  61 , Sara Gutiérrez-Enríquez  20 , Thomas Haaf  56 , Karl Hackmann  62 , Thomas V O Hansen  57 , Marion Harris  63 , Jan Hauke  3   4 , Tilman Heinrich  51 , Heide Hellebrand  60 , Karen N Herold  64 , Ellen Honisch  65 , Judit Horvath  66 , Claude Houdayer  67 , Verena Hübbel  3   4 , Silvia Iglesias  5 , Angel Izquierdo  5 , Paul A James  36   68 , Linda A M Janssen  69 , Udo Jeschke  42 , Silke Kaulfuß  70 , Katharina Keupp  3   4 , Marion Kiechle  60 , Alexandra Kölbl  42 , Sophie Krieger  71   72   73 , Torben A Kruse  74 , Anders Kvist  22 , Fiona Lalloo  49 , Mirjam Larsen  3   4 , Vanessa L Lattimore  75 , Charlotte Lautrup  76   77 , Susanne Ledig  66 , Elena Leinert  78 , Alexandra L Lewis  79 , Joanna Lim  80 , Markus Loeffler  25 , Adrià López-Fernández  15 , Emanuela Lucci-Cordisco  81 , Nicolai Maass  10 , Siranoush Manoukian  14 , Monica Marabelli  21 , Laura Matricardi  7 , Alfons Meindl  42 , Rodrigo D Michelli  55 , Setareh Moghadasi  69 , Alejandro Moles-Fernández  20 , Marco Montagna  7 , Gemma Montalban  20 , Alvaro N Monteiro  82 , Eva Montes  5 , Luigi Mori  83 , Lidia Moserle  7 , Clemens R Müller  56 , Christoph Mundhenke  10 , Nadia Naldi  23 , Katherine L Nathanson  43 , Matilde Navarro  5 , Heli Nevanlinna  84 , Cassandra B Nichols  85 , Dieter Niederacher  65 , Henriette R Nielsen  74 , Kai-Ren Ong  86 , Nicholas Pachter  85   87 , Edenir I Palmero  88   89 , Laura Papi  29 , Inge Sokilde Pedersen  77   90   91 , Bernard Peissel  14 , Pedro Perez-Segura  26 , Katharina Pfeifer  60 , Marta Pineda  5 , Esther Pohl-Rescigno  3   4 , Nicola K Poplawski  53   92 , Berardino Porfirio  29 , Anne S Quante  60 , Juliane Ramser  60 , Rui M Reis  88   93   94 , Françoise Revillion  95 , Kerstin Rhiem  3   4 , Barbara Riboli  33 , Julia Ritter  44 , Daniela Rivera  24 , Paula Rofes  5 , Andreas Rump  62 , Monica Salinas  5 , Ana María Sánchez de Abajo  96 , Gunnar Schmidt  12 , Ulrike Schoenwiese  25 , Jochen Seggewiß  66 , Ares Solanes  5 , Doris Steinemann  12 , Mathias Stiller  97 , Dominique Stoppa-Lyonnet  30   98   99 , Kelly J Sullivan  100 , Rachel Susman  13 , Christian Sutter  18 , Sean V Tavtigian  101   102 , Soo H Teo  80   103 , Alex Teulé  5 , Mads Thomassen  74 , Maria Grazia Tibiletti  32 , Marc Tischkowitz  104 , Silvia Tognazzo  7 , Amanda E Toland  105 , Eva Tornero  5 , Therese Törngren  22 , Sara Torres-Esquius  15 , Angela Toss  17 , Alison H Trainer  36   106 , Katherine M Tucker  107   108 , Christi J van Asperen  69 , Marion T van Mackelenbergh  10 , Liliana Varesco  24 , Gardenia Vargas-Parra  5 , Raymonda Varon  44 , Ana Vega  19 , Ángela Velasco  5 , Anne-Sophie Vesper  65 , Alessandra Viel  34 , Maaike P G Vreeswijk  109 , Sebastian A Wagner  110 , Anke Waha  3   4 , Logan C Walker  75 , Rhiannon J Walters  1 , Shan Wang-Gohrke  78 , Bernhard H F Weber  111 , Wilko Weichert  112 , Kerstin Wieland  25 , Lisa Wiesmüller  78 , Isabell Witzel  113 , Achim Wöckel  114 , Emma R Woodward  48   49 , Silke Zachariae  25 , Valentina Zampiga  115 , Christine Zeder-Göß  42 ; KConFab Investigators  68   116 ; Conxi Lázaro  5 , Arcangela De Nicolo  117 , Paolo Radice  118 , Christoph Engel  25 , Rita K Schmutzler  3   4 , David E Goldgar  119 , Amanda B Spurdle  1
Affiliations

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

Michael T Parsons et al. Hum Mutat. 2019 Sep.

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.

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

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Conflict of interest statement

The following authors declare conflicts as stated below.

Sandrine M. Caputo: Astra Zeneca contributes financially to the COVAR study.

Laura Cortesi: Astra Zeneca (honoraria), Pfizer (honoraria and advisory role), Amgen (advisory role), and Novartis (advisory role).

Fergus Couch: Steering committee and diagnostics committee for the Astra Zeneca LUCY study.

Anne‐Marie Gerdes: February 2016, advisory Board meeting about BRCA1/2 testing in ovarian cancer, sponsored by Astra Zenica.

Paolo Radice: Scientific coordinator of a course on the classification of BRCA gene allele variants sponsored by Astra Zeneca (Milan, June 2018).

Angela Toss: Lilly (advisory role), Roche (advisory role).

Lisa Wiesmuller is an inventor of a patent on a test system for determining genotoxicities, which is owned by LW.

Ana Vega: October 2015, advisory Board meeting about BRCA1/2 testing in ovarian cancer, sponsored by Astra Zeneca.

All other authors declare that they have no conflict of interests.

References

    1. Antoniou, A. , Pharoah, P. D. P. , Narod, S. , Risch, H. A. , Eyfjord, J. E. , Hopper, J. L. , … Easton, D. F. (2003). Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: A combined analysis of 22 studies. American Journal of Human Genetics, 72(5), 1117–1130. - PMC - PubMed
    1. Antoniou, A. C. , Cunningham, A. P. , Peto, J. , Evans, D. G. , Lalloo, F. , Narod, S. A. , … Southey, M. C. (2008). The BOADICEA model of genetic susceptibility to breast and ovarian cancers: Updates and extensions. British Journal of Cancer, 98(8), 1457–1466. - PMC - PubMed
    1. Bouwman, P. , van der Gulden, H. , van der Heijden, I. , Drost, R. , Klijn, C. N. , Prasetyanti, P. , … Hogervorst, F. B. (2013). A high‐throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discovery, 3(10), 1142–1155. - PubMed
    1. Breast Cancer Linkage C . (1999). Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute, 91(15), 1310–1316. - PubMed
    1. Cline, M. S. , Babbi, G. , Casadio, R. , Katsonis, P. , Lai, C. , Lichtarge, O. , …, O'Conner, R. Manuscript submitted for publication. Assessment of blind predictions of the clinical significance of BRCA variants. Human Mutation. - PMC - PubMed

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