Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing

Breast Cancer Res Treat. 2019 Dec;178(3):557-564. doi: 10.1007/s10549-019-05429-z. Epub 2019 Sep 11.


Purpose: In order to better define the breast cancer (BC) genetic risk factors in men, a germline investigation was carried out on 81 Male BC cases by screening the 24 genes involved in BC predisposition, genome stability maintenance and DNA repair mechanisms by next-generation sequencing.

Methods: Germline DNAs were tested in a custom multi-gene panel focused on all coding exons and exon-intron boundaries of 24 selected genes using two amplicon-based assays on PGM-Ion Torrent (ThermoFisher Scientific) and MiSeq (Illumina) platforms. All variants were recorded and classified by using a custom pipeline.

Results: Clinical pathological data and the family history of 81 Male BC cases were gathered and analysed, revealing the average age of onset to be 61.3 years old and that in 35 cases there was a family history of BC. Our genetic screening allowed us to identify a germline mutation in 22 patients (23%) in 4 genes: BRCA2, BRIP1, MUTYH and PMS2. Moreover, 12 variants of unknown clinical significance (VUS) in 9 genes (BARD1, BRCA1, BRIP1, CHEK2, ERCC1, NBN, PALB2, PMS1, RAD50) were predicted as potentially pathogenic by in silico analysis bringing the mutation detection rate up to 40%.

Conclusion: As expected, a positive family history is a strong predictor of germline BRCA2 mutations in male BC. Understanding the potential pathogenicity of VUS represents an extremely urgent need for the management of BC risk in Male BC cases and their own families.

Keywords: Breast cancer risk in men; DNA repair genes; Familial breast cancer; Male breast cancer; Next-generation sequencing.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms, Male / blood
  • Breast Neoplasms, Male / genetics*
  • Breast Neoplasms, Male / pathology
  • DNA Repair / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genetic Variation*
  • Genome, Human / genetics
  • Germ-Line Mutation
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Pedigree


  • Neoplasm Proteins