Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

Int J Mol Sci. 2022 Sep 29;23(19):11499. doi: 10.3390/ijms231911499.


The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.

Keywords: Hereditary Breast and Ovarian Cancer Syndrome (HBOC); Lynch Syndrome (LS); double heterozygotes; genetic counseling; multi-gene panel testing.

Publication types

  • Case Reports

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms* / diagnosis
  • Breast Neoplasms* / genetics
  • Carcinoma, Ovarian Epithelial / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
  • Female
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Mismatch Repair Endonuclease PMS2 / genetics
  • Mutation
  • Ovarian Neoplasms* / diagnosis
  • Ovarian Neoplasms* / genetics


  • BRCA1 Protein
  • BRCA2 Protein
  • Mismatch Repair Endonuclease PMS2

Grant support

This research was funded by the Regional Government of Castilla y León through the University of Valladolid, Valladolid (Spain). Regional Health Management of Castilla y León, Grants: GRS/2180/A/2020 and GRS/2351/A/2021. Donation from Charity Calendar 2022 of Pedrajas de San Esteban, Valladolid (Spain). Donation from Juan Victor Oncology Association of Santa Marta de los Barros, Badajoz (Spain).