Submission Details

The gene RET is associated with the autosomal dominant disorder multiple endocrine neoplasia type 2A characterized by medullary thyroid cancer, pheochromocytoma and parathyroid tumors first reported in 1993 (Mulligan et al, 1993; PMID: 8099202). Early evidence began to show linkage of multiple endocrine neoplasia type 2 (not discerning between type A vs. type B) as early as 1992 (Narod et al., 1992; PMID: 2572534). Numerous variants have been reported in RET in relation to multiple endocrine neoplasia type A , the majority being missense mutation in conserved cysteine (p. Cys or p.C) amino acid residues within the dimerization and activation domain, including p.C609, p.C611, p.C618, p. C620, p. C630, p.C634 (reviewed Plaza-Menaho et al., 2006; PMID: 16979782). The molecular mechanism for the RET-multiple endocrine neoplasia type 2A is gain of function (GOF), as the missense mutations result in ligand-independent dimerization that induces activation of the RET protein that is a receptor tyrosine kinase (Plaza-Menaho et al., 2006; PMID: 16979782; Drilon et al., 2017, PMID 29134959). There are variant databases specific to the RET gene including the Multiple Endocrine Neoplasia type 2 (MEN2) and RET database (http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php) and the RET gene LOVD database (https://databases.lovd.nl/shared/genes/RET). Substantial evidence supports this gene-disease relationship includes case-level data, segregation and experimental data with the maximum score (12) for genetic evidence reached. This gene-disease relationship is supported by functional studies including expression, cell assays and animal models, several that were patient derived pathogenic variants expressed in the mouse (reviewed in Wiedmann et al, 2016; PMID: 26184857). These animal models developed MEN2A related tumors including medullary thyroid carcinomas. The RET gene is asserted to be associated with multiple disease entities by germline inheritance, including: (1) Central hypoventilation syndrome, congenital (MIM:209880), (2) Medullary thyroid carcinoma (MIM:155240), (3) Multiple endocrine neoplasia IIB (MIM:162300), (4) Pheochromocytoma (MIM:171300). These disease entities all follow an autosomal dominant inheritance pattern. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found no difference in molecular mechanisms, inheritance pattern, or phenotypic expressivity between Medullary thyroid carcinoma (MIM:155240), Pheochromocytoma (MIM:171300), and multiple endocrine neoplasia type 2A (MIM:171400), and therefore have lumped the above listed disease entities into the curation for RET in Multiple Endocrine neoplasia type 2A. Of note, Multiple endocrine neoplasia IIB (MIM:162300) follows a different GOF mechanism and has variants specific to this disease entity and has been curated separately. Due to variants asserted in Medullary thyroid carcinoma (MIM:155240), Pheochromocytoma (MIM:171300) with both multiple endocrine neoplasia type 2A and type 2B, the evidence for each of these was lumped into the appropriate gene-disease relationship based on the variant asserted for the evidence. Furthermore, Central hypoventilation syndrome, congenital (MIM:209880) has distinct variants associated with it and also has a separate curation. However, it should be noted that CCHS can be a phenotypic feature observed in individuals with multiple endocrine neoplasia, so care was taken in the curation and assessing evidence based on the variant of interest asserted. In addition, the Hirsphrung disease which is associated with LOF in RET is not included in this curation. In summary, RET is DEFINITIVELY associated with autosomal dominant multiple endocrine neoplasia type 2A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.