Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families

Genet Med. 2018 Dec;20(12):1677-1686. doi: 10.1038/s41436-018-0005-9. Epub 2018 Jul 10.


Purpose: Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.

Methods: Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.

Results: Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01-17.22], 8.61 [6.78-10.82], 8.22 [4.91-13.05], 4.54 [2.55-7.48], 5.23 [1.46-13.17], 3.20 [2.14-4.53], 2.49 [1.42-3.97], 1.67 [1.18-2.27], and 2.50 [1.12-4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78-19.59], 12.44 [2.94-33.30] and 3.82 [1.66-7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48-34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37-25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.

Conclusion: Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.

Keywords: HBOC; genetic risk estimation; panel gene sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • DNA-Binding Proteins / genetics*
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • France / epidemiology
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genetic Variation / genetics
  • Hereditary Breast and Ovarian Cancer Syndrome / diagnosis
  • Hereditary Breast and Ovarian Cancer Syndrome / epidemiology
  • Hereditary Breast and Ovarian Cancer Syndrome / genetics*
  • Hereditary Breast and Ovarian Cancer Syndrome / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Risk Factors
  • Whole Exome Sequencing


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Neoplasm Proteins
  • PALB2 protein, human
  • RAD51C protein, human
  • RAD51D protein, human