Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2

Gynecol Oncol. 2015 Apr;137(1):86-92. doi: 10.1016/j.ygyno.2015.01.537. Epub 2015 Jan 23.


Objective: Genetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel.

Methods: Subjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort.

Results: In this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%).

Conclusions: Although further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.

Keywords: BRCA1; BRCA2; Hereditary; Lynch syndrome; Multi-gene; Next-generation sequencing.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Breast Neoplasms / genetics
  • Checkpoint Kinase 2 / genetics
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genes, p53
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Middle Aged
  • Mutation*
  • Ovarian Neoplasms / genetics*
  • RNA Helicases / genetics
  • Young Adult


  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group Proteins
  • G-T mismatch-binding protein
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • BRIP1 protein, human
  • RNA Helicases