Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in BRCA2

Genes (Basel). 2023 Feb 15;14(2):502. doi: 10.3390/genes14020502.

Abstract

Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).

Keywords: BRCA2; HBOC; constitutional mosaicism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA2 Protein / genetics
  • Female
  • Genes, BRCA2
  • Hereditary Breast and Ovarian Cancer Syndrome* / genetics
  • Humans
  • Mosaicism
  • Mutation
  • Ovarian Neoplasms* / genetics

Substances

  • BRCA2 protein, human
  • BRCA2 Protein

Grants and funding

Project “PI19/00340” to L.R., funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. MdlH lab is supported by a grant from the Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I 2013-2016, ISCIII (PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union).