부산대학교 도서관

Simple Summary: Variants of uncertain significance in the breast cancer susceptibility gene BRCA2 represent 50–80% of the results from genetic testing. These mutations may lead to the dysfunction of the gene, thus conferring breast cancer predisposition; however, because they are rare and their impact on the function is not easy to predict, their classification into benign or pathogenic variants remains a challenge. By focusing on three specific rare missense variants identified in breast cancer patients, in this review, we discuss how the functional evaluation of this type of variants can be used to reveal novel activities of BRCA2. Based on these findings, we suggest additional functional tests that might be required for accurate variant classification and how their characterization may be leveraged to find novel clinical strategies for patients bearing these mutations. The breast cancer susceptibility gene BRCA2 encodes a multifunctional protein required for the accurate repair of DNA double-strand breaks and replicative DNA lesions. In addition, BRCA2 exhibits emerging important roles in mitosis. As a result, mutations in BRCA2 may affect chromosomal integrity in multiple ways. However, many of the BRCA2 mutations found in breast cancer patients and their families are single amino acid substitutions, sometimes unique, and their relevance in cancer risk remains difficult to assess. In this review, we focus on three recent reports that investigated variants of uncertain significance (VUS) located in the N-terminal region of BRCA2. In this framework, we make the case for how the functional evaluation of VUS can be a powerful genetic tool not only for revealing novel aspects of BRCA2 function but also for re-evaluating cancer risk. We argue that other functions beyond homologous recombination deficiency or "BRCAness" may influence cancer risk. We hope our discussion will help the reader appreciate the potential of these functional studies in the prevention and diagnostics of inherited breast and ovarian cancer. Moreover, these novel aspects in BRCA2 function might help find new therapeutic strategies. [ABSTRACT FROM AUTHOR]