Analysis of Newly Identified and Rare Synonymous Genetic Variants in the RET Gene in Patients with Medullary Thyroid Carcinoma in Polish Population

Abstract

Gain-of-function germline mutations of the RET proto-oncogene are responsible for initiation of carcinogenesis within the thyroid gland and development of hereditary form of medullary thyroid carcinoma and MEN2 syndrome. Genotype-phenotype correlations are established for most RET mutations, but the importance of the synonymous changes in this gene remains debatable. We aimed to analyze RET gene variants in Polish population. Genetic testing for the RET gene variants was performed with standard methods in 585 people aged 1–85, including 448 patients with medullary thyroid carcinoma and 131 of their first- and second-degree relatives, as well as six patients suspected of MTC/MEN2. Besides the most frequent synonymous changes, p.Leu769Leu, p.Ser836Ser, and p.Ser904Ser, four rare changes—c.1827C>T (p.Cys609Cys), c.2364C>T (p.Ile788Ile), c.2418C>T (p.Tyr806Tyr), and c.2673G>A (p.Ser891Ser)—were found in the RET gene, in the Polish population. Two of the rare changes, p.Cys609Cys and p.Ile788Ile, had not been previously described. The frequency of molecular synonymous variants in the general population was evaluated by testing 400 anonymous blood samples of neonates. Our findings may contribute to a better understanding of the genetic diversity of the RET gene and the involvement of synonymous variants in this diversity.Electronic supplementary materialThe online version of this article (doi:10.1007/s12022-017-9487-2) contains supplementary material, which is available to authorized users.

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

“…However, it is interesting that an I788S variant found in a 43-year-old patient with MTC was predicted to be “damaging”, while the substitution is considered to be of UCS according to ACMG-2015 guidelines. In addition, a 46-year-old patient with MTC was reported to have the synonymous heterozygous variant I788I [c.2364C > T] [ 49 ], implying that I788S may be a UCS or a potentially pathogenic mutation. Two patients diagnosed at 44 and 46 years, respectively, had an A604S variant classified as UCS depending on the 3 algorithms used and following the ACMG-2015.…”

Relationship between polymorphism in the tumour necrosis factor-alpha gene and selected indices and cell subpopulations in naturally bovine leukaemia virus-infected and healthy cows

“…However, recent studies have revealed several mechanisms by which synonymous changes may affect protein function and cause numerous diseases (Sromek et al 2017). Synonymous mutations, similarly to pathogenic nonsense and missense mutations, change the dynamics of the corresponding proteins in the TNFα signalling network, leading to a significant increase in the critical dose of TNFα necessary for cell death (Sromek et al 2017).…”