Functional evaluation and clinical classification of BRCA2 variants

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…

• CC
  Conquer Cancer Foundation
• BC
  Breast Cancer Research Foundation

  Awards: R35CA253187, P50CA116201
• SJ
  Sigrid Juséliuksen Säätiö

  Awards: R35CA253187, P50CA116201
• NI
  National Institutes of Health

  Awards: K12CA090628, P50CA116201, R01CA225662, R35CA253187