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Multiple endocrine neoplasia type 2 kindred with novel tandem RET mutations: Case report with an applied in silico mutational tolerance analysis
Author(s) -
Joshi Rohan R.,
Heineman Thomas E.,
Kutler David I.,
Cohen Marc A.,
Kuhel William I.
Publication year - 2016
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.24340
Subject(s) - in silico , multiple endocrine neoplasia type 2 , multiple endocrine neoplasia , mutation , thyroid carcinoma , mutation testing , biology , germline mutation , genetics , proto oncogene proteins c ret , hyperplasia , pheochromocytoma , cancer research , thyroid , endocrinology , gene , receptor , neurotrophic factors , glial cell line derived neurotrophic factor
Background The American Thyroid Association (ATA) has established guidelines for prophylactic thyroidectomy in multiple endocrine neoplasia type 2A (MEN2A) based on rearranged during transfection ( RET ) mutations. In silico analysis, which uses computer modeling to predict alterations in protein structure, is a new method for studying these mutations. Methods We describe a kindred with MEN2A, all sharing a well‐documented RET mutation, p.C634Y, as well as a mutation of undetermined significance, p.I852M, which we analyzed via in silico analysis. Results The p.C634Y mutation resulted in severe predicted RET alterations, whereas the p.I852M resulted in only modest changes. Both mutations together resulted in only a small additional disruptive effect in protein structure beyond that which occurred with p.C634Y alone. Conclusion Although in silico analysis may be helpful in quantitating changes in protein structure that occur in patients who have novel RET mutations (single or multiple), additional factors must account for the highly variable aggressiveness of the disease (C‐cell hyperplasia/medullary thyroid carcinoma [MTC]) noted in our kindred. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E1881–E1885, 2016