AUTHOR=Alonso Natalia , Menao Sebastián , Lastra Rodrigo , Arruebo María , Bueso María P. , Pérez Esther , Murillo M. Laura , Álvarez María , Alonso Alba , Rebollar Soraya , Cruellas Mara , Arribas Dolores , Ramos Mónica , Isla Dolores , Galano-Frutos Juan José , García-Cebollada Helena , Sancho Javier , Andrés Raquel 

TITLE=Association between missense variants of uncertain significance in the CHEK2 gene and hereditary breast cancer: a cosegregation and bioinformatics analysis

JOURNAL=Frontiers in Genetics

VOLUME=Volume 14 - 2023

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1274108

DOI=10.3389/fgene.2023.1274108

ISSN=1664-8021

ABSTRACT=Inherited mutations in the CHEK2 gene have been associated with an increased lifetime risk of developing breast cancer (BC).  We aim to identify in the study population the prevalence of mutations in CHEK2 gene in  diagnosed BC patients, to evaluate the phenotypic characteristics of the tumor and family history, and to predict the deleteriousness of the variants of uncertain significance (VUS). A genetic study was performed, from May 2016 to April 2020, in 396 patients diagnosed of BC at the University Hospital Lozano Blesa of Zaragoza (Spain). Patients with a genetic variant in the CHEK2 gene were selected for the study. We performed a descriptive analysis of the clinical variables, a bibliographic review of the variants and a cosegregation study when possible. Moreover, an in depth bioinformatics analysis on CHEK2 VUS was carried out. We identified 9 genetic variants in the CHEK2 gene, in 10 patients (2 pathogenic variants and 7 VUS). This supposes a prevalence of 0.75% and 1.77% respectively. In all cases there was a family history of BC in first and /or second-degree relatives. We carried out a cosegregation study in two families, being positive in one of them. The bioinformatics analyses predicted the pathogenicity of 6 of the VUS. In conclusion, CHEK2 mutations have been associated with increased risk for BC. This risk is well established for foundation variants. However, the risk assessment for other variants is unclear. The incorporation of bioinformatics analysis provided supporting evidence of the pathogenicity of VUS.