RET mutation Tyr791Phe: the genetic cause of different diseases derived from neural crest

Abstract

Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

“…Interestingly, all 6 of the MTC patients with a codon 791 mutation in this study are part of the same kindred from Brazil (55). The index case did have sequencing of RET exons 8, 10, 11, and [13][14][15][16], though the relatives were tested only for the presence of the 791 mutation, making it possible but unlikely that another deleterious RET mutation [52][53][54][55][56][57][58][59][60] [CI], 95% confidence interval; NA, not reached.…”

Genotype-phenotype correlation in multiple endocrine neoplasia type 2

“…VUS are RET sequence changes in which there is not enough clinical evidence to indicate a causative role, so further clinical studies, in vitro experiments (e.g., kinase activity assay), and prediction algorithms are necessary to clarify whether the sequence change is a mutation or a polymorphism. One example of this is the S649L and Y791F RET germline sequence variants that have been described and verified as mild mutations by some ()()(26-28) and as non-pathogenic by others (29). Using the Bayes classification to predict the disease associations of uncertain gene variants into categories of benign and pathogenic, amino acid-substitution penalties, structural disruption, sequence homology (e.g., ortholog conservation) or neural nets, the RET Y791N sequence changes are classified as pathogenic (30).…”

Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2

“…The significance of the Y791F mutation remains somewhat controversial. Reports have identified this mutation, alone or in combination with other mutations, in MEN 2A and FMTC, and in sporadic MTC and pheochromocytoma tumors (24),(75). Co-occurrence of Y791F and codon 634 mutations has been shown to increase the risk of pheochromocytoma in some families (76), whereas other studies have concluded that this mutation is not pathogenic (77).…”

“…Co-occurrence of Y791F and codon 634 mutations has been shown to increase the risk of pheochromocytoma in some families (76), whereas other studies have concluded that this mutation is not pathogenic (77). Interestingly, a clue is perhaps provided by studies identifying Y791F and Y791N mutations in patients with Hirschsprung disease (75),(78),(79), possibly suggesting that mutations of tyrosine 791 may act as modifiers of multiple phenotypes.…”