Beyond 1100delC: distinct CHEK2 variants and unique cancer phenotypes in Northeast Brazil

The CHEK2 gene confers a moderate risk for breast cancer, but existing knowledge is largely based on the European founder variant, 1100delC. This study aimed to characterize the distinct phenotypes associated with unique CHEK2 variants in Brazilian families. In this cross-sectional study, 1055 patients meeting criteria for Hereditary Breast and Ovarian Cancer syndrome underwent germline multigene panel testing. Pathogenic/likely pathogenic variants (PVs) were found in 141 patients (13.4%), of whom 13 (9.2%) had a CHEK2 PVs. Subsequent family cascade testing brought the total number of individuals studied to 57. Three distinct CHEK2 PVs were identified: c.846 + 1G > C, c.349 A > G, and c.593-1G > T. While breast cancer was the most frequent tumor, specific PVs correlated with different cancer spectra. The c.349 A > G variant showed an enrichment for papillary thyroid cancer. In contrast, the c.846 + 1G > C variant was associated with melanoma, prostate, and testicular cancer, in addition to breast, colon, and kidney cancers. These findings suggest that different CHEK2 PVs may confer distinct cancer risks. Investigating these variants across diverse populations is crucial for refining phenotype characterization and improving genetic counseling as access to genetic testing expands.