PLOS ONE: Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants

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Introduction

Between 10 and 20% of the breast cancer cases appearing in the general population present familial history of the disease [1]. Mutations in BRCA1 and BRCA2 genes confer high lifetime risks of breast and ovarian cancer, among other neoplasias [2], [3]. Inactivating germline mutations in these genes account for 20–50% of familial cases, depending on the population [4]. Thus, genetic analysis of BRCA1 and BRCA2 is a cornerstone of genetic counseling practice. However, classification of genetic variants as pathogenic is challenging, particularly for missense changes and for silent or intronic variants that cannot be directly associated with increased cancer risk and are classified as variants of uncertain significance (VUS), which are found in 13% of BRCA1 and BRCA2 genetic tests [5]......