Spleen tyrosine kinase (SYK) is a non-receptor type cytoplasmic protein and a known tumor suppressor genein breast cancer. Polymorphisms in SYK have been reported to be associated with cell invasion/cell moralityand an increased risk of cancer development. In this case control study, all exons of the SYK gene and its exon/intron boundaries were amplified in 200 breast cancer cases and 100 matched controls and then analyzed bysingle stranded conformational polymorphism. Amplified products showing altered mobility patterns weresequenced and analyzed. Twelve variations were identified in exonic and intronic regions of DNA encoding SH2domain and kinase domain of the SYK gene. All of these mutations are novel. Among them, 5 missense mutationswere observed in exon 15 while one missense mutation was found in exon 8. In addition to these mutations, sixmutations were also identified in intronic regions. We found a significant association between SYK mutationsand breast cancer and observed that Glu241Arg, a missense mutation is associated with an increase risk of ~7fold (OR=6.7, 95% CI=1.54-28.8), Thr581Pro (missense mutation) is associated with increased risk of ~16 fold(OR=15.5, 95%CI=2.07-115.45) and 63367 T>G (missense mutation) is associated with increased risk of ~13fold (OR=12.8, 95%CI=1.71-96.71) for breast cancer. Significant associations were observed for each of thesevariations with both late menopause (p<0.01) and early menarche (p<0.005) cases when compared to controls.Our findings suggest that the polymorphic gene SYK may contribute to the development of breast cancer inat least the Pakistani population. This study provides an insight view of SYK which may provide a significantfinding for the pharmaceutical and biotechnology industry.