Variants of uncertain clinical significance in BRCA1, BRCA2, and other genes of the homologous DNA repair system: epidemiology, interpretation and clinical significance

In recent decades, the study of germline mutations in genes involved in homologous DNA repair, including BRCA1 and BRCA2 and a number of others, has become crucial in clinical oncology practice. These mutations are associated with a significantly increased risk of developing malignant neoplasms, primarily in the breast and ovaries. However, with the development of mass molecular genetic testing, variants of uncertain clinical significance are increasingly being identified. The interpretation of these variants is difficult due to limited functional data, an insufficient representation of ethnic groups in reference databases and ambiguous classification criteria. This complicates the task even for experienced specialists. Due to the fact that a high proportion of rare and previously undescribed variants leads to an inflated number of mutations defined as VUS (variant of uncertain significance), it is difficult to make clinical decisions and choose preventive or therapeutic tactics. The article analyzes modern approaches to interpreting VUS mutations in key genes, provides an overview of their epidemiology in different populations, discusses complexities associated with personalized patient management, and suggests ways to improve the informative value of molecular genetic studies in oncology.