Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants

Hum Mutat. 2019 Sep;40(9):1546-1556. doi: 10.1002/humu.23861. Epub 2019 Aug 23.


Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

Keywords: BRCA; BRCA1; BRCA2; CAGI; CAGI5; variant interpretation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics
  • Computational Biology / methods*
  • Early Detection of Cancer
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genetic Variation
  • Humans
  • Models, Genetic
  • Ovarian Neoplasms / diagnosis*
  • Ovarian Neoplasms / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human