Functional evaluation and clinical classification of BRCA2 variants

Huaizhi Huang, Chunling Hu (), Jie Na, Steven N. Hart, Rohan David Gnanaolivu, Mohamed Abozaid, Tara Rao, Yohannes A. Tecleab, Tina Pesaran, Paulo Cilas Morais Lyra, Rachid Karam, Siddhartha Yadav, Katherine L. Nathanson, Susan M. Domchek, Miguel Hoya, Mark Robson, Miika Mehine, Chaitanya Bandlamudi, Diana Mandelker, Alvaro N. A. Monteiro, Edwin S. Iversen, Nicholas Boddicker, Wenan Chen, Marcy E. Richardson and Fergus J. Couch ()
Additional contact information
Huaizhi Huang: Mayo Clinic
Chunling Hu: Mayo Clinic
Jie Na: Mayo Clinic
Steven N. Hart: Mayo Clinic
Rohan David Gnanaolivu: Mayo Clinic
Mohamed Abozaid: Mayo Clinic
Tara Rao: Mayo Clinic
Yohannes A. Tecleab: Mayo Clinic
Tina Pesaran: Ambry Genetics
Paulo Cilas Morais Lyra: H. Lee Moffitt Cancer Center
Rachid Karam: Ambry Genetics
Siddhartha Yadav: Mayo Clinic
Katherine L. Nathanson: Perelman School of Medicine at the University of Pennsylvania
Susan M. Domchek: Perelman School of Medicine at the University of Pennsylvania
Miguel Hoya: Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Mark Robson: Memorial Sloan Kettering Cancer Center
Miika Mehine: Memorial Sloan Kettering Cancer Center
Chaitanya Bandlamudi: Memorial Sloan Kettering Cancer Center
Diana Mandelker: Memorial Sloan Kettering Cancer Center
Alvaro N. A. Monteiro: H. Lee Moffitt Cancer Center
Edwin S. Iversen: Duke University
Nicholas Boddicker: Mayo Clinic
Wenan Chen: Mayo Clinic
Marcy E. Richardson: Ambry Genetics
Fergus J. Couch: Mayo Clinic

Nature, 2025, vol. 638, issue 8050, 528-537

Abstract: Abstract Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers1–5. However, variants of uncertain significance limit the clinical utility of test results. Thus, there is a need for functional characterization and clinical classification of all BRCA2 variants to facilitate the clinical management of individuals with these variants. Here we analysed all possible single-nucleotide variants from exons 15 to 26 that encode the BRCA2 DNA-binding domain hotspot for pathogenic missense variants. To enable this, we used saturation genome editing CRISPR–Cas9-based knock-in endogenous targeting of human haploid HAP1 cells6. The assay was calibrated relative to nonsense and silent variants and was validated using pathogenic and benign standards from ClinVar and results from a homology-directed repair functional assay7. Variants (6,959 out of 6,960 evaluated) were assigned to seven categories of pathogenicity based on a VarCall Bayesian model8. Single-nucleotide variants that encode loss-of-function missense variants were associated with increased risks of breast cancer and ovarian cancer. The functional assay results were integrated into models from ClinGen, the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology9 for clinical classification of BRCA2 variants. Using this approach, 91% were classified as pathogenic or likely pathogenic or as benign or likely benign. These classified variants can be used to improve clinical management of individuals with a BRCA2 variant.

Date: 2025
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DOI: 10.1038/s41586-024-08388-8

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