Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer

Cancer Res. 2020 Feb 15;80(4):857-867. doi: 10.1158/0008-5472.CAN-19-1991. Epub 2019 Dec 10.


Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ 2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60-3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. SIGNIFICANCE: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

Publication types

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

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Alleles
  • Breast Neoplasms / blood
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Cohort Studies
  • DNA Mutational Analysis
  • Datasets as Topic
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Germ-Line Mutation
  • HeLa Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Loss of Function Mutation
  • Middle Aged
  • Mutation, Missense
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / genetics*
  • RNA Helicases / genetics*


  • Fanconi Anemia Complementation Group Proteins
  • BRIP1 protein, human
  • RNA Helicases