Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer

Paula S. Felicio, Rebeca S. Grasel, Natalia Campacci, Andre E. de Paula, Henrique C.R. Galvão, Giovana T. Torrezan, Cristina S. Sabato, Gabriela C. Fernandes, Cristiano P. Souza, Rodrigo D. Michelli, Carlos E. Andrade, Bruna Durães De Figueiredo Barros, Marcus M. Matsushita, Timothée Revil, Jiannis Ragoussis, Fergus J. Couch, Steven N. Hart, Rui M. Reis, Matias E. Melendez, Patricia N. ToninDirce M. Carraro, Edenir I. Palmero

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

Original languageEnglish (US)
Pages (from-to)290-299
Number of pages10
JournalHuman mutation
Issue number3
StatePublished - Mar 2021


  • breast cancer predisposition
  • hereditary breast and ovarian cancer predisposition syndrome
  • hereditary cancer
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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