PTEN missense mutation that results in the substitution of cysteine at position 124 with serine affects the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain. The cystein residue in this motif, corresponding to C124 of human PTEN, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). PTEN C124S (Cys124Ser) mutant shows markedly decreased phosphoinositide phosphatase activity (Koul et al. 2002).