[en] The prevalence study of Hereditary Breast and Ovarian Cancer (HBOC) carried out in 2928 families in the Region of Murcia has identified the recurrent pathogenic variants and founder mutations, mainly associated with the BRCA1 and BRCA2 genes. The variants c.68_69del, c.212+1G>A, and c.5123C>A were detected in 30% of BRCA1 carriers while exon 2 deletion along with c.3264dupT, c.3455T> G and c.9117G>A have been found in 30% of BRCA2 carriers. The genotype-phenotype correlation did not show differences with respect to what was previously reported in the literature for BRCA1/2 carriers. In addition, this thesis demonstrates the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) in the Murcian population and exon2 deletion (BRCA2) as a Spanish founder mutation. The incorporation of genetic panels through massive sequencing in healthcare practice has led to a significant increase in detected variants of unknown clinical significance. The implementation of a VUS prioritization algorithm in Genomics Laboratory of University Hospital Virgen de la Arrixaca, based on the clinical actionability of the genes and the predictions estimated by the computational tools, has made it possible to prioritize 16 variants susceptible to pathogenicity (15%). The study of prioritized VUS through reverse transcription-polymerase chain reaction, RT-PCR/capillary electrophoresis and RT-PCR/Sanger, has allowed us to characterize the prioritized variants susceptible to aberrant or alternative splicing. The presence of 1 aberrant splicing event has been demonstrated, classifying the variant c.3402+3A<C (ATM) as probably pathogenic. The presence of 2 alternative splicing events of the variants c.8488-1_8489delinsTCCATTACA (BRCA2) and c.320-5T>A (CHEK2) has been evidenced. Likewise, it has been proven that the variant c.1008G>A (CHEK2) does not modify the constitutive splicing pattern. Therefore, the probability that they are pathogenic variants is reduced, and it is appropriate to consider them as VUS.

[es] El estudio de prevalencia del Síndrome de Cáncer de Mama y Ovario Hereditario (SCMOH) realizado en 2928 familias de Región de Murcia ha permitido identificar las variantes patogénicas recurrentes y mutaciones fundadoras, principalmente asociadas a los genes BRCA1 y BRCA2. Las variantes c.68_69del, c.212+1G>A, y c.5123C>A fueron detectadas en un 30% de los portadores de BRCA1 mientras que la deleción del exón 2 junto con c.3264dupT, c.3455T>G y c.9117G>A se han encontrado en un 30% de los portadores de BRCA2. La correlación genotipo-fenotipo no mostró diferencias con respecto a lo reportado previamente en la literatura para portadores de BRCA1/2. Además, esta tesis demuestra el efecto fundador de c.1918C>T (BRCA1) y c.8251_8254del (ATM) en la población murciana y la deleción del exon2 (BRCA2) como mutación fundadora española. La incorporación de paneles genéticos mediante secuenciación masiva en la práctica asistencial ha derivado en el incremento significativo de variantes de significado clínico desconocido detectadas. La implementación de un algoritmo de priorización de VUS en el Laboratorio de Genómica del Hospital Clínico Universitario Virgen de la Arrixaca, basado en la accionabilidad clínica de los genes y en las predicciones estimadas por las herramientas computacionales, ha permitido priorizar 16 variantes susceptibles de patogenicidad (15%). El estudio de VUS priorizadas mediante reacción en cadena de la polimerasa con transcriptasa reversa, RT-PCR/electroforesis capilar y RT-PCR/Sanger, ha permitido caracterizar las variantes priorizadas susceptibles de splicing aberrante o alternativo. Se ha demostrado la presencia de 1 evento de splicing aberrante, clasificando la variante c.3402+3A<C (ATM) como probablemente patogénica. Se ha evidenciado la presencia de 2 eventos de empalme alternativo de las variantes c.8488-1_8489delinsTCCATTACA (BRCA2) y c.320-5T>A (CHEK2). Asimismo, se ha comprobado que la variante c.1008G>A (CHEK2) no modifica el patrón de empalme constitutivo. Por tanto, se reduce la probabilidad de que sean variantes patogénicas, y deben ser consideradas como VUS.