The CHEK2-1100delC mutation is recurrent in the population and is a moderate 
risk factor for breast cancer. To identify additional CHEK2 mutations 
potentially contributing to breast cancer susceptibility, we sequenced 248 cases 
with early-onset disease; functionally characterized new variants and conducted 
a population-based case-control analysis to evaluate their contribution to 
breast cancer risk. We identified 1 additional null mutation and 5 missense 
variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant 
resulted in gross protein destabilization, while others had variable suppression 
of in vitro kinase activity using BRCA1 as a substrate. The germline 
CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) 
early-onset and 3/302 (1%) familial breast cancer cases, but undetectable 
amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive 
breast cancer families also carried a deleterious BRCA1 mutation. 1100delC 
appears to be the only recurrent CHEK2 mutation associated with a potentially 
significant contribution to breast cancer risk in the general population. 
Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not 
associated with increased breast cancer susceptibility, but exhibits a striking 
difference in frequency across populations with different ancestral histories. 
These observations illustrate the importance of genotyping ethnically diverse 
groups when assessing the impact of low-penetrance susceptibility alleles on 
population risk. Our findings highlight the notion that clinical testing for 
rare missense mutations within CHEK2 may have limited value in predicting breast 
cancer risk, but that testing for the 1100delC variant may be valuable in 
phenotypically- and geographically-selected populations.