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

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).

Automated summary

Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical condition with increased risks of breast and ovarian cancer. Genetic diagnosis is based on identifying heterozygous germinal variants in HBOC susceptibility genes. Recently, constitutional mosaic variants have been found to contribute to the development of HBOC. These variants occur early in development, affecting multiple tissues, and are often overlooked during genetic studies. They can be passed to offspring and impact genetic counseling. This study reports a specific mosaic variant and proposes a diagnostic algorithm for identifying mosaic findings via Next Generation Sequencing (NGS).