New genes and genetic variants discovery in hereditary cancer: functional, splicing assays and population frequency of variants for their use in the clinic

Genetic susceptibility to breast and ovarian cancer (BC/OV) affects a large number of patients and families in our country and is a major health problem. With the analysis of the well-known related genes, a molecular diagnosis is not obtained in a large number of families, with consequent problems in the subsequent genetic counselling and clinical follow. This may be due to that the full spectrum of genes responsible for hereditary cancer is unknown as well as to the significant proportion of detected genetic variants without biological and clinical significance (VUS).
We propose:
-the validation of candidate genes selected from 24 BRCAX Spanish families exomes, in 2000 Spanish families and 500 controls (1000 from each participating centre of the coordinated project, ICO and Vall d’Hebron);
-the interpretation of exonic genetic variants of uncertain clinical significance by analysing effects on splicing enhancer regions (ESEs), whose effect is underestimated in most current studies;
-the development of a functional assay to evaluate the VUS effect on protein activity for its clinical application.
The results will make a contribution to the knowledge of the genetic susceptibility to BC/OV with a direct and immediate application in the diagnosis and genetic counselling of patients and their families as well as the precision of your personalized treatment.