Although the pathogenic variant, CHEK2 p.S428F with lower LC risk is not statistically significant in the meta-analysis, its protective effect is consistent with another known pathogenic low-frequency variant, CHEK2 p.I157T, associated with reduced risk of smoking-related cancers (lung, laryngeal, urinary, and upper aerodigestive tract)18,73–75. This evidence concerns the gene CHEK2 and cancer.