Rare, evolutionarily unlikely missense substitutions in CHEK2contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study

This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.