Abstract
Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.
Highlights
MEN2 (MIM #164761) is a dominantly inherited multiglandular tumour syndrome that presents with a high penetrance of medullary thyroid carcinoma (MTC; observed in virtually 100% of cases), phaeochromocytoma (50%) and parathyroid adenoma and/or hyperplasia (20%) (Eng et al 1996)
The role of rearranged during transfection (RET) Y791F-only in MTC/MEN2related pathogenesis and susceptibility is currently a matter of dispute (Vestergaard et al 2007, Kloos et al 2009, Eng 2010, Erlic et al 2010, Rich et al 2014 and Supplementary References, see section on supplementary data given at the end of this article)
The analyses of 22 138 alleles from the control subjects revealed that Y791F is a very rare SNP, with a frequency that varies greatly among the analysed populations (Fig. 1 and Supplementary Table 1, see section on supplementary data given at the end of this article)
Summary
MEN2 (MIM #164761) is a dominantly inherited multiglandular tumour syndrome that presents with a high penetrance of medullary thyroid carcinoma (MTC; observed in virtually 100% of cases), phaeochromocytoma (50%) and parathyroid adenoma and/or hyperplasia (20%) (Eng et al 1996). Biased genetic analyses of highly selected patients, in addition to relatively small numbers of controls, may result in a misunderstanding and misclassification of the pathogenicity of rare variants of medically actionable genes (Weber & Eng 2005) In this context, there is currently a great debate in the literature regarding the potential pathogenicity of the c.2372AOT Y791F variant in exon 13 of RET (Berndt et al 1998, Fitze et al 2002, 2004, Gimm et al 2002, Brauer et al 2004, Plaza-Menacho et al 2007, Tamanaha et al 2007, Vestergaard et al 2007, Eng 2010, Erlic et al 2010, Cerutti & Maciel 2013, Peczkowska et al 2013, Rich et al 2014). All of the data from the databases were obtained between 20 July and 23 July 2014, and the websites for each database are listed at the end of the article
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