A founder CHEK2 pathogenic variant in association with kidney cancer

The gene CHEK2 is located at 22q12.1 and codes for the protein checkpoint kinase 2, a protein that functions in cell cycle regulation and is a known tumor suppressor. CHEK2 is activated due to DNA damage generating a cascade of protein phosphorylation events involving key mediators such as Cdc25A, Cdc25C, and BRCA1. The phosphorylation of these substrates leads to cell cycle arrest, DNA repair, or apoptosis. Pathogenic variants in the gene CHEK2 are known to be associated with an increased lifetime risk for developing male and female breast, colorectal, and prostate cancer. Preliminary literature suggests certain pathogenic variants in the gene CHEK2 may be associated with an increased lifetime risk for developing other cancers, such as papillary thyroid cancer. Four studies in the literature support that a pathogenic variant in the gene CHEK2 may lead to an increased lifetime risk of developing clear cell renal carcinoma. Our patient has a personal history of clear cell renal and gastric cancer, a family history of clear cell renal and breast cancer, and a IVS2+1G>A pathogenic variant in CHEK2. This case study supports the limited evidence that pathogenic variants in CHEK2 may be associated with an increased lifetime risk of developing clear cell renal carcinoma. Further investigation into this association could impact the recommended genetic testing and medical management for individuals with a personal or family history of clear cell renal cancer.