title: The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A.
abstract: The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Qreveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Grey
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Rosaline
authors.initials: R
authors.lastname: Hulse
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Yakovleva
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Dilyana
authors.initials: D
authors.lastname: Genkova
authors.affiliation: Clinical Endocrinology, King's College Hospital London, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Whitelaw
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.affiliation: Histopathology, King's College Hospital London, London, UK.
authors.forename: Salvador J
authors.initials: SJ
authors.lastname: Diaz-Cano
authors.affiliation: Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK. louise.izatt@gstt.nhs.uk.|Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust London, Great Maze Pond, London, SE1 9RT, UK. louise.izatt@gstt.nhs.uk.
authors.forename: Louise
authors.identifier: http://orcid.org/0000-0003-1258-4843
authors.initials: L
authors.lastname: Izatt
mesh_terms: D000328:Adult; D015153:Blotting, Western; D005260:Female; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010375:Pedigree; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: C-cell hyperplasia; Hirschsprung; MEN2A; Phaeochromocytoma; RET proto-oncogene