Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women

The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques.Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73).The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.Breast cancer is the most common form of malignancy amongst females in the western world. Specifically, one in ten of all new diagnosed cancer cases are of the female breast [1]. Typically, less than five percent of these cases are inherited in a mendelian fashion, specifically from the segregation of highly penetrant alleles, such as mutations in BRCA1 and BRCA2 [2]. The existence of a large number of breast cancer families who lack linkage to either BRCA1 or BRCA2 [3] suggested that other breast cancer susceptibility genes remained undiscovered. One such candidate gene, CHEK2, encodes a multifunctional kinase enzyme involved in the induction of cell cycle arrest, DNA repair and apoptosis [4-6]. Several large-scale studies have characterized known variants of the CHEK2 gene [7-9], conclusively proving that CHEK2 is a breast cancer susceptibility gene.One CHEK2 mutation present in the general population, 1100delC, occurs independently of BRCA1/2 mutations [7,8]. The 1100delC variant results in a premature stop codon withi