PTEN missense mutation that results in the substitution of arginine at position 130 with leucine 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 arginine residue in this motif, corresponding to R130 of human PTEN, is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130L (Arg130Leu) mutant shows markedly decreased phosphoinositide phosphatase activity (Han et al. 2000). PTEN R130L is found as a germline mutation in Cowden syndrome, an autosomal dominant cancer syndrome (Marsh et al. 1998).