A RET double mutation in the germline of a kindred with FMTC

Activating germline mutations of the RET protooncogene are found in more th an 90% of families with multiple endocrine neoplasia type 2a (MEN 2a) and f amilial medullary thyroid carcinoma (FMTC). The majority of patients with t hese heriditary tumors carry germline mutations that result in the substitu tion of one of five cysteine residues in exon 10 and 11. Different mutation s in exons 13, 13 and 15 affecting non-cysteine residues have also been des cribed but are considered to be rare. We now for the first time report a do uble mutation of the RET protooncogene occuring in the germline of a kindre d with FMTC. Both mutations occur within the tyrosine kinase domain in exon 14 and lead to the substitution of valine 804 by methionine and arginine 8 44 by leucine. Since the double mutated allele cosegregated with the diseas e and was not identified in 200 unrelated normal probands, we conclude that they represent mutations that predispose the individual to the development of FMTC with a mild phenotype.