Functional, Structural and Contextual Analysis of A Variant of Uncertain Clinical Significance in Brca1: C.5434c->g (p. Pro1812ala) - Functional, Structural and Contextual Analysis of A Variant of Uncertain Clinical Significance in Brca1: C.5434c->g (p. Pro1812ala) - Open Access Pub

Interpreting variants of uncertain significance (VUS) for their effect on protein function, and therefore for the risk of developing cancer, has become a challenge in clinical practice for genetic counselling services. The present work combines structural bioinformatics and systems biology based mathematical modelling approaches with the aim of determining the pathogenicity of the mutation c.5434C->G (p.Pro1812Ala) in the BRCA1 gene (detected in a patient from a high risk family) and also to mechanistically understand the effect of this mutation in DNA damage response, a key process in cancer development. The results obtained showed that this mutation prevents the interaction of BRCA1 with key proteins of the cell cycle, subsequently impairing BRCA1-dependent induction of cell cycle arrest. The comparison of the molecular mechanisms associated with the native BRCA1 protein and the mutated variant function in DNA damage response showed that the latter undergoes a reduction in its ability to modulate pathways that are critical for DNA repair and cell cycle control. Therefore, this variant will not be able to exert its tumor suppressive action. Interestingly, these conclusions can be extrapolated to all mutations that, like c.5434C>G (p.Pro1812Ala) BRCA1, cause loss of BRCT domain activity. DOI10.14302/issn.2572-3030.jcgb-16-1307 Deleterious variants in the BRCA1 and BRCA2 genes account for approximately 20% of cases of hereditary breast and ovarian cancer. The BRCA1 gene is found on the long arm of chromosome 17 (17q21) and plays a crucial role in DNA damage response. BRCA1 inactivating mutations lead to genetic instability, indirectly causing tumours to occur as a result of an accumulation of mutations in cell cycle regulatory genes. In Spain, families that carry the deleterious mutation in the BRCA1 gene have a 52% cumulative risk of developing breast cancer and a 22% risk of developing ovarian cancer by the age of 70 1. The BRCA1 protein is a protein of 1863 amino acids. The two most important domains of BRCA1 are the RING domain and the BRCT domain. The RING domain is located at the amino terminus of BRCA1, between amino acids 1 and 109 (exons 2 - 7), and it is responsible for the E3·ubiquitin·ligase activity of BRCA1 2 and binds to the BARD1 protein. The BRCT domain mediates binding with phosphorylated proteins such as: Abraxas 3, 4, BACH1/BRIP1 5, and CtlP 6, forming three mutually exclusive protein complexes named A, B and C complexes (see below). A number of other proteins also bind to the C-terminal region of BRCA1 and/or its central region 7