Table 4.

Molecular effects of RET mutations in multiple endocrine neoplasia 2.

Mutation location	Affected RET Codons	Putative function of the wild-type residue	Predicted mutation effects	Phenotype	Recommended intervention
Extracellular-cysteine rich domain	C609	Contributes to tertiary structure of RET through the formation of intramolecular disulfide bonds	Weakly activating. Alteration in protein folding and maturation.Formation of mutant RET dimers that are constitutively active in the absence of ligands	MEN 2A and FMTC	Prophylactic thyroid surgery before the age of 5.
	C611
	C618
	C620				Under some conditions may delay beyond 5 years
	C630
	C634	Role in formation of intramolecular disulfide bonds	Strongly activating. Ligand-independent dimerization of receptor molecules, enhanced phosphorylation of intracellular substrates.	MEN 2A	Surgery <5 years
Intracellular tyrosine kinase domain	L790, Y791	In the N-terminal lobe of the RET kinase	Moderately activating. Affects ATP binding and inter-lobe flexibility.	MEN 2A and FMTC	May delay surgery beyond 5 years
	E768	In close proximity with the ATP binding site	Alters interactions within the region and facilitates the transition to an active conformation	FMTC
	V804	A gatekeeper residue which regulates access to the ATP binding site	Alters hinge flexibility and positioning of RET helices for catalysis	FMTC
	S891	C-terminal lobe of the kinase, adjacent to the activation loop of the kinase	Alters activation loop conformation and promotes monomeric RET activation	MEN 2A and FMTC
	A883	Situated next to activation loop	Strongly activating. Local conformational change which destabilizes the inactive form of the protein and promotes its activation	MEN 2B	As early as possible (within first year of life)
	M918	Lies in the substrate-binding pocket of the kinase and plays a role in stabilizing the receptor–ATP complex	Strongly activating. Alters protein conformation and substrate specificity. The mutant can dimerize and become phosphorylated in the absence of ligand stimulation	MEN 2B

FMTC, familial medullary thyroid carcinoma; MEN 2, multiple endocrine neoplasia 2; RET, REarranged during Transfection.