Background: Inherited mutations in the CHEK2 gene have been associated with an increased lifetimerisk of develop breast cancer (BC). The main objective of the study is to identify in our population the prevalence of mutations in the CHEK2 gene in diagnosed BC patients, as well as to evaluate the phenotypic characteristics of the tumour and family history. Methods: A genetic study was performed in 396 patients diagnosed of BC at the University Hospital Lozano Blesa of Zaragoza (Spain). We selected 9 patients with genetic variants in the CHEK2 gene and performed a descriptive analysis of the clinical variables, a bibliographic review of the genetic variants and a co-segregation study. Results: We identified 2 pathogenic variants (CHEK2 c.349 A>G and c.507delT) and 6 variants of uncertain significance (VUS). The genotypic characteristics of the VUS are summarized in the table. In all cases there was a family history of BC in first and /or second degree relatives. The variant cosegregated with the disease in one of the families. Conclusions: The pathogenic missense variant c.349A>G was found in two families. This is a rare missense variant. Studies have shown that this variant had a significant impact on the protein based on in silico prediction and has been associated with BC. In our study, this variant was found in a patient with renal carcinoma and was identified in a proband with a strong family history of pancreatic and ovarian cancer (OC). However, there aren’t exist data about the risk of developing other cancer, different of BC, with this specific mutation. The other pathogenic variant detected was CHEK2 c.507delT in a family with history of BC and OC. This variant is a frameshift mutation, predicted to cause loss of normal protein function. CHEK2 507delT was reported in one of 12 BC families in one series and is possible its relation with OC. With regard to the VUS the cosegregation analysis in selected families may help understand if a variant could have played a role in developing cancer. In conclusion, CHEK2 mutations have been associated with increased risk for BC. However, the frequency of carriers may vary depending on the population, and different mutations may be associated with different cancer risks. More studies are needed to establish a complete range of risks associated with CHEK2 mutations.

gnomAD: The Genome Aggregation Database.