Abstract 7325: Integration of functional data to classify BRCA1/2 missense variants: An ENIGMA project

Cancer Research, vol. 84, pp. 7325

Abstract

Abstract The success of precision cancer prevention and treatment hinges on accurate discrimination between benign and pathogenic germline alleles in cancer susceptibility genes. Variants of uncertain clinical significance (VUS) present a challenge for cancer risk assessment and functional data will be essential to resolve many VUS. To address this, we developed a cloud-based environment to collate, curate, integrate and analyze all published functional data related to BRCA1 and BRCA2 missense VUS. Then, functional evidence criteria for pathogenicity were determined for each assay using the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) classification guidelines and ClinGen criteria. Our approach involved retrieving published articles reporting one or more functional assays of BRCA1/2 missense variants reporting variant impact on various biochemical and cell biological functions. Functional results were recorded using original authors' thresholds and categories, then converted to ordinal variables to harmonize: [0 = no functional impact], [1 = intermediate impact], and [2 = functional impact]. For BRCA1, we updated our previous published integration (Genet Med. 2021;23:306-315) with 14 additional publications, collating results from 53 instances of functional assays reporting functional data on 3,219 unique missense variants. For BRCA2, 28 publications were identified reporting data from 141 instances of functional assays on 4,759 unique missense variants. Utilizing a panel of 542 and 396 known pathogenic and benign reference variants for BRCA1 and BRCA2, respectively, we determined the sensitivity, specificity, and ACMG/AMP odds of pathogenicity for each instance of the assay. The remaining variants were assigned a relevant functional assay code weight for each assay instance. Our study successfully derived ACMG/AMP evidence strength from functional data for 3,040 BRCA1 (94% of 3,219) and 2,704 BRCA2 (57% of 4,759) missense variants. This comprehensive work underscores the utility of functional data in informing classification of BRCA1 and BRCA2 missense VUS. Citation Format: Paulo Lyra, Lucas Dalcolmo, Michael Parsons, Thales Nepomuceno, Samuel Brito, Nam Phuong N. Nguyen, Geise de Oliveira, Joao Paulo da Siva, Laura Caleca, Tanisha Taneja, Chunling Hu, Marcy Richardson, Maria Rossing, Aditi Hazra, Alexandra Martins, Sandrine Caputo, Gael A. Millot, Joanne NgeowYuen Yie, Marcelo A. Carvalho, Melissa Cline, Paolo Radice, Rachael Carlsen, Romy Mesman, Valentina Zampiga, Rehan Villani, Vijay Josef, Shyam Sharan, Kyriaki Michailidou, Amanda B. Spurdle, Fergus Couch, Maaike P.G. Vreeswijk, Alvaro N. Monteiro. Integration of functional data to classify BRCA1/2 missense variants: An ENIGMA project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7325.

Authors 32

1. Paulo Cilas Morais Lyra Junior

   Moffitt Cancer Center

   Affiliation as printed

   1Moffitt Cancer Center, Tampa, FL;

2. Lucas Dalcolmo

   Moffitt Cancer Center

   Affiliation as printed

   1Moffitt Cancer Center, Tampa, FL;

3. Michael T. Parsons

   QIMR Berghofer Medical Research Institute

   Affiliation as printed

   2QIMR Berghofer Medical Research Institute, Brisbane, Australia;

4. Thales C. Nepomuceno

   Moffitt Cancer Center

   Affiliation as printed

   1Moffitt Cancer Center, Tampa, FL;

5. Samuel Gomes Brito

   Moffitt Cancer Center

   Affiliation as printed

   1Moffitt Cancer Center, Tampa, FL;

6. Nam Phuong N. Nguyen

   Moffitt Cancer Center

   Affiliation as printed

   1Moffitt Cancer Center, Tampa, FL;

7. Geise de Oliveira
   Affiliation as printed

   3Centro Universitario FAEMA, Ariquemes, Brazil;

8. Joao Paulo da Siva
   Affiliation as printed

   3Centro Universitario FAEMA, Ariquemes, Brazil;

9. Laura Caleca

   Fondazione IRCCS Istituto Nazionale dei Tumori

   Affiliation as printed

   4Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;

10. Tanisha Taneja

    Moffitt Cancer Center

    Affiliation as printed

    1Moffitt Cancer Center, Tampa, FL;

11. Chunling Hu

    Mayo Clinic

    Affiliation as printed

    5Mayo Clinic, Rochester, MN;

12. Marcy E. Richardson

    Ambry Genetics (United States)

    Affiliation as printed

    6Ambry Genetics, Aliso Viejo, CA;

13. Maria Rossing

    University of Copenhagen

    Affiliation as printed

    7Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;

14. Aditi Hazra

    Harvard University

    Affiliation as printed

    8Harvard University, Boston, MA;

15. Alexandra Martins

    Inserm · Université de Rouen Normandie

    Affiliation as printed

    9Inserm U1245 Université de Rouen, Rouen, France;

16. Sandrine M. Caputo

    Institut Curie

    Affiliation as printed

    10Institut Curie, Paris, France;

17. Gaël A. Millot

    Institut Pasteur

    Affiliation as printed

    11Institut Pasteur, Paris, France;

18. Joanne Ngeow Yuen Yie

    National Cancer Centre Singapore

    Affiliation as printed

    12National Cancer Centre Singapore, Singapore, Malaysia;

19. Marcelo Alex Carvalho

    Instituto Nacional de Câncer - INCA

    Affiliation as printed

    13Instituto Nacional de Cancer, Rio de Janeiro, Brazil;

20. Melissa Cline

    University of California, Santa Cruz

    Affiliation as printed

    14University of California, Santa Cruz Genomic Institute, Santa Cruz, CA;

21. Paolo Radice

    Fondazione IRCCS Istituto Nazionale dei Tumori

    Affiliation as printed

    4Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;

22. Rachael Carlsen

    Quest Diagnostics (United States)

    Affiliation as printed

    15Quest Diagnostics, Secaucus, NJ;

23. Romy L.S. Mesman Aachen

    Leiden University Medical Center

    Affiliation as printed

    16Leiden University Medical Center, Leiden, Netherlands;

24. Valentina Zampiga

    Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

    Affiliation as printed

    17IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy;

25. Rehan Marie Villani

    QIMR Berghofer Medical Research Institute

    Affiliation as printed

    2QIMR Berghofer Medical Research Institute, Brisbane, Australia;

26. Vijay Josef
    Affiliation as printed

    18Memorial Sloan Kettering, New York, NY;

27. Shyam K. Sharan

    National Cancer Institute · Center for Cancer Research

    Affiliation as printed

    19Center for Cancer Research, National Cancer Institute, Fredrick, MD;

28. Kyriaki Michailidou

    Cyprus Institute of Neurology and Genetics

    Affiliation as printed

    20Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

29. Amanda B. Spurdle

    QIMR Berghofer Medical Research Institute

    Affiliation as printed

    2QIMR Berghofer Medical Research Institute, Brisbane, Australia;

30. Fergus J. Couch

    Mayo Clinic

    Affiliation as printed

    5Mayo Clinic, Rochester, MN;

31. Maaike P.G. Vreeswijk Aachen

    Leiden University Medical Center

    Affiliation as printed

    16Leiden University Medical Center, Leiden, Netherlands;

32. Álvaro N.A. Monteiro

    Moffitt Cancer Center

    Affiliation as printed

    1Moffitt Cancer Center, Tampa, FL;