Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2

Int J Cancer. 2017 Jan 1;140(1):95-102. doi: 10.1002/ijc.30428. Epub 2016 Sep 23.


Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2, we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes.

Keywords: breast cancer; gene panel; next generation sequencing; non-BRCA1/2; ovarian cancer.

MeSH terms

  • Age of Onset
  • BRCA1 Protein / genetics
  • BRCA2 Protein
  • Breast Neoplasms / genetics*
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Germany
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Mutation*
  • Nuclear Proteins / genetics
  • Ovarian Neoplasms / genetics*
  • Sequence Analysis, DNA / methods*
  • Tumor Suppressor Proteins / genetics
  • White People / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins

Supplementary concepts

  • Breast Cancer, Familial