Purpose: BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. Methods: We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/ Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. Results: Integration of data from validated assays provided ACMG/ AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. Conclusion: High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

No abstract

Ovarian cancer is a leading cause of gynecological cancer-related deaths in women worldwide, mainly because of its late diagnosis. In many cases, at the time of diagnosis, the cancer cells are chemoresistant and invasive. Early detection of the disease is crucial for a clinically satisfactory outcome, treatment planning, and a better prognosis. The development of new strategies for early detection may contribute to improving overall survival in patients. Inflammation is an established factor in carcinogenesis, and protein complexes named inflammasomes, along with their components and subproducts, such as interleukins and other molecules, have been explored as promising potential Note to the reader: This chapter is part of the book Ovarian Cancer

No abstract