Affiliation:
1. Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
2. Molecular Genetics Unit, Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy
Abstract
BRCA1, a crucial tumor suppressor gene, has several splicing isoforms, including Δ9–11, Δ11, and Δ11q, which lack exon 11, coding for significant portions of the protein. These isoforms are naturally present in both normal and cancerous cells, exhibiting altered activity compared to the full-length BRCA1. Despite this, the impact on cancer risk of the germline intronic variants promoting the exclusive expression of these Δ11 isoforms remains uncertain. Consequently, they are classified as variants of uncertain significance (VUS), posing challenges for traditional genetic classification methods due to their rarity and complexity. Our research utilizes a yeast-based functional assay, previously validated for assessing missense BRCA1 variants, to compare the activity of the Δ11 splicing isoforms with known pathogenic missense variants. This approach allows us to elucidate the functional implications of these isoforms and determine whether their exclusive expression could contribute to increased cancer risk. By doing so, we aim to provide insights into the pathogenic potential of intronic VUS-generating BRCA1 splicing isoforms and improve the classification of BRCA1 variants.