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Accurate classification of BRCA1 variants with saturation genome editing

Author

Listed:
  • Gregory M. Findlay

    (University of Washington)

  • Riza M. Daza

    (University of Washington)

  • Beth Martin

    (University of Washington)

  • Melissa D. Zhang

    (University of Washington)

  • Anh P. Leith

    (University of Washington)

  • Molly Gasperini

    (University of Washington)

  • Joseph D. Janizek

    (University of Washington)

  • Xingfan Huang

    (University of Washington)

  • Lea M. Starita

    (University of Washington
    Brotman Baty Institute for Precision Medicine)

  • Jay Shendure

    (University of Washington
    Brotman Baty Institute for Precision Medicine
    University of Washington)

Abstract

Variants of uncertain significance fundamentally limit the clinical utility of genetic information. The challenge they pose is epitomized by BRCA1, a tumour suppressor gene in which germline loss-of-function variants predispose women to breast and ovarian cancer. Although BRCA1 has been sequenced in millions of women, the risk associated with most newly observed variants cannot be definitively assigned. Here we use saturation genome editing to assay 96.5% of all possible single-nucleotide variants (SNVs) in 13 exons that encode functionally critical domains of BRCA1. Functional effects for nearly 4,000 SNVs are bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. Over 400 non-functional missense SNVs are identified, as well as around 300 SNVs that disrupt expression. We predict that these results will be immediately useful for the clinical interpretation of BRCA1 variants, and that this approach can be extended to overcome the challenge of variants of uncertain significance in additional clinically actionable genes.

Suggested Citation

  • Gregory M. Findlay & Riza M. Daza & Beth Martin & Melissa D. Zhang & Anh P. Leith & Molly Gasperini & Joseph D. Janizek & Xingfan Huang & Lea M. Starita & Jay Shendure, 2018. "Accurate classification of BRCA1 variants with saturation genome editing," Nature, Nature, vol. 562(7726), pages 217-222, October.
  • Handle: RePEc:nat:nature:v:562:y:2018:i:7726:d:10.1038_s41586-018-0461-z
    DOI: 10.1038/s41586-018-0461-z
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    Citations

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    Cited by:

    1. Federica Luppino & Ivan A. Adzhubei & Christopher A. Cassa & Agnes Toth-Petroczy, 2023. "DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Elizabeth J. Radford & Hong-Kee Tan & Malin H. L. Andersson & James D. Stephenson & Eugene J. Gardner & Holly Ironfield & Andrew J. Waters & Daniel Gitterman & Sarah Lindsay & Federico Abascal & Iñigo, 2023. "Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Craig Smail & Bing Ge & Marissa R. Keever-Keigher & Carl Schwendinger-Schreck & Warren A. Cheung & Jeffrey J. Johnston & Cassandra Barrett & Keith Feldman & Ana S. A. Cohen & Emily G. Farrow & Isabell, 2024. "Complex trait associations in rare diseases and impacts on Mendelian variant interpretation," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Liselot Dewachter & Aaron N. Brooks & Katherine Noon & Charlotte Cialek & Alia Clark-ElSayed & Thomas Schalck & Nandini Krishnamurthy & Wim Versées & Wim Vranken & Jan Michiels, 2023. "Deep mutational scanning of essential bacterial proteins can guide antibiotic development," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Shiqiang Jin & Gyuhyeong Goh, 2021. "Bayesian selection of best subsets via hybrid search," Computational Statistics, Springer, vol. 36(3), pages 1991-2007, September.
    7. Lukas Gerasimavicius & Benjamin J. Livesey & Joseph A. Marsh, 2022. "Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Annabel K. Sangree & Audrey L. Griffith & Zsofia M. Szegletes & Priyanka Roy & Peter C. DeWeirdt & Mudra Hegde & Abby V. McGee & Ruth E. Hanna & John G. Doench, 2022. "Benchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Luke Hoberecht & Pirunthan Perampalam & Aaron Lun & Jean-Philippe Fortin, 2022. "A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    11. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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