Human homologues of mouse cancer modifier genes may play a role in cancer risk and prognosis. A proportion of the familial risk of common cancers may be attributable to variants in such genes, each contributing to a small effect. The protein tyrosine phosphatase receptor type J (PTPRJ) has been recently identified as being the protein encoded by the Scc1 mouse gene (susceptibility to colon cancer-1). In addition, the PTPRJ gene has been shown to be somatically altered in several human cancer types such as colon, lung and breast cancers and to have the characteristics of a tumour-suppressor gene. The purpose of this study was to determine whether common variants in the PTPRJ gene represent low penetrance breast cancer susceptibility alleles. To test this hypothesis, we assessed single nucleotide polymorphisms (SNPs) tagging the common SNPs and haplotypes of the gene in 4512 cases and 4554 controls from the East Anglian population. We observed a difference in the haplotype frequency distributions between cases and controls (P = 0.0023, OR = 0.81 [0.72-0.92]). Thus, carrying a specific PTPRJ haplotype confers a protective effect on the risk of breast cancer. This result establishes the principle that mouse cancer modifier genes are candidates for low penetrance human breast cancer susceptibility genes.