Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study

Introduction Both protein-truncating variants and some missense substitutions in CHEK2 confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in CHEK2 to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions.