Table 2.
Congenital Syndromes Associated with Mutational Alterations of Components of Ras Signaling Pathways
| Syndrome | Mutated Gene | Protein Function | Mutations/Other Changes Observed | Associated Neoplasias |
|---|---|---|---|---|
| Neurofibromatosis type1156,185 | NF1 (Neurofibromin) | RasGAP | Small and large deletions; insertions; mutations throughout the protein; intron mutations have also been described. Nonsense R1947X mutation is the most frequent event (~ 2%) | Increased cancer risk: neurofibrosarcomas, central nervous system tumors, myeloid leukemias |
| Leopard syndrome147,157,173 | PTPN11 (SHP2) | RTK phosphatase | Y279C/S, A461T, G464A, T468M/P, R498W/L, Q506P, Q510P/E/G | Myelodysplasia, acute myelogenous leukemia, neuroblastoma |
| RAF1 (c-Raf) | Kinase | S257L, L613V | ||
| B-RAF (B-Raf) | Kinase | T241P, L245F | ||
| Noonan syndrome149,161,166 | PTPN11 (SHP2) | RTK phosphatase | Over 58 different mutations. The most frequent: D61N/G, Y63C/G, A72S/G, T73I, E76D, Q79R, E139D, Y279C, N308D/S, T468M, M504V | Cancer an uncommon outcome of the illness; higher risk of myeloproliferative disease and leukemia, especially juvenile myelomonocytic leukemia |
| SOS1 (Sos1) | RasGEF | T266K, M269R/T, D309Y, Y337C, G434R, C441Y, P478 R/L, S548R, L550P, R552G/K/S, F623I, P655L, Y702H, W729L, I733F, E846K | ||
| K-RAS (K-Ras) | GTPase | V14I, Q22R, P34L/Q, I36M, T58I, V152G, D153V, F156I | ||
| N-RAS (N-Ras) | GTPase | T50I, G60E | ||
| RAF1 (c-Raf) | Kinase | R256S, S257L, S259F, T260R/I, P261S/L/A, V263A, D486N/G, T491I/R, S612T, L613V | ||
| B-RAF (B-Raf) | Kinase | E501K, K499E, L597V | ||
| SHOC2 (SHOC2) | Scaffold | S2G | ||
| MEK1 (MEK1) | Kinase | D67N | ||
| Legius syndrome170,186 | SPRED1 (SPRED1) | Interactor | Deletions; amino acid switching mutations: V44D, S149N, M1T; nonsense mutations: R16X, R64X, E73X, R117X, Q213X, Q215X, K322X, R325X | Possible increased risk of cancer |
| Costello syndrome14,173 | H-RAS (H-Ras) | GTPase | G12S/A/V/C/E, G13C, K117R, A146T | Rhabdomyosarcoma, transitional cell carcinoma, neuroblastoma |
| K-RAS (K-Ras) | GTPase | K5N, V152G, F156L | ||
| B-RAF (B-Raf) | Kinase | G534R, D638E | ||
| Cardio-facio-cutaneous syndrome150,173 | K-RAS (K-Ras) | GTPase | Q22E, P34R, G60R, D153V, F156I | Cancer predisposition uncertain; possible acute lymphoblastic leukemia |
| B-RAF (B-Raf) | Kinase | A246P, Q257K/R, S467A, F468S, G469E, L485F, V487G, K499E, E501K/G, G534R, N580D, N581D, F595L, G596V, D638E | ||
| MEK1 (MEK1) | Kinase | F53S, P124L, Y130C | ||
| MEK2 (MEK2) | Kinase | F57C, K61E, P128R, G132V | ||
| Hereditary gingival fibromatosis type 1180 | SOS1 (Sos1) | RasGEF | Single nucleotide insertion (C) between nt 3248 and nt 3249 | No increased risk of cancer |
| Autoimmune lymphoproliferative syndrome182 | N-RAS (N-Ras) | GTPase | G13D | Increased risk of hematological malignancies |
| Capillary malformation– arteriovenous malformation183,187 | Rasa1 (p120RasGAP) | RasGAP | Deletions; duplications; and mutations: G829A, C853T, C1336T, Q446X, C540Y, G1619A | Vascular tumors |
See accompanying text and references for more detailed information about symptoms and mechanisms involved in the development of each syndrome.