1165 – Identification of a novel pathogenic germline variant in the BRCA2 gene in patients with hereditary breast and ovarian cancer syndrome

Abstract

Introduction: Hereditary breast and ovarian cancer (HBOC) syndrome is associated with pathogenic variants in the
BRCA1 and BRCA2 genes, which are essential for DNA repair and the maintenance of genomic integrity. Thousands of
variants have been described in BRCA2, with more than 5,000 classified as pathogenic in public databases. Alterations in
this gene significantly increase the risk of neoplasms, especially breast cancer. The identification of novel germline variants is essential to improve molecular diagnosis, genetic counseling, and clinical management.
Methods: This observational study involved patients with clinical suspicion of HBOC treated at the Human Genetics
Center of the Federal University of Goiás. Genomic DNA samples extracted from peripheral blood were analyzed. BRCA2
sequencing was performed using next-generation sequencing. Identified variants were analyzed using bioinformatics
tools, compared with data from public databases (ClinVar and gnomAD), and classified according to the guidelines of the
American College of Medical Genetics and Genomics (ACMG).
Results: A 48-year-old female patient diagnosed with invasive ductal breast carcinoma was referred for oncogenetic evaluation. The BRCA2 variant c.4245_4246insA was identified and classified as likely pathogenic. This alteration consists of
an insertion with the potential to cause a frameshift, resulting in a truncated protein and probable loss of function. The
variant was neither found in population databases nor previously described in the scientific literature, supporting its rare
and possibly novel nature.
Conclusion: The identification of this novel germline variant reinforces the central role of BRCA2 in hereditary breast
cancer predisposition and highlights the importance of genetic testing in individuals with clinical suspicion of HBOC.
This finding contributes to the enrichment of genomic databases and to advances in oncogenetics, with further studies
being needed for better functional and clinical characterization.
Ethics: Research Ethics Committee Approval (CAAE 50626315.6.3001.0031).
Funding: Goiás State Health Secretariat (SES-GO), Coordination for the Improvement of Higher Education Personnel
(CAPES), Brazilian Agency for Financing Studies and Projects (FINEP), National Council for Scientific and Technological
Development (CNPq), Brazilian National Genomics and Precision Health Program (Genomas Brazil).