The power of association studies between polymorphic genetic variants and breast cancer may be enhanced if the cancer subjects are subclassified by histologic subgroup. In this study we classified 482 unselected breast cancers from Szczecin, Poland by histology (ductal, lobular, medullary, other). All women were genotyped for three founder mutations in the CHEK2 gene (1100delC, IVS2 + 1G > A and I157T). There was no significant overall association between CHEK2 and breast cancer (OR = 1.3; p = 0.30), but among those with lobular carcinoma the association with the I157T missense mutation was very strong (OR = 6.6; p > 0.0001). This is the first report to demonstrate that different mutations of the same gene may be associated with specific histologic subtypes of cancer.