Submission Details

The gene RET was first reported in relation to autosomal dominant multiple endocrine neoplasia type 2B (MEN2B) characterized by very early onset medullary thyroid cancer, pheochromocytoma, parathyroid tumors and dysmorphic features first reported in in 1994 (Hofstra et al, 1994 PMID:7906866; Carlson et al. 1994 PMID:7977365). Earlier evidence suggested that the disease MEN2B mapped to chromosome 10 (where the RET gene is located) as early as 1990 (Norum et al., 1990 PMID:1979053). One variant, p.Met918Thr, is responsible for nearly all cases of MEN2B, and it is estimated that around 50% of the reported cases of MEN2B are de novo (Carlson et al. 1994 PMID:7977365; Plaza-Menaho et al., 2006; PMID: 16979782). Another RET variant (p. Ala883Phe) has been asserted to be responsible for the development of ~5% of MEN2B (Smith et al., 1997 PMID:9294615). The molecular mechanism for the gene RET in the disease entity MEN2B is gain of function. While similar to RET-MEN2A (described in a separate curation), in that the mechanism is GOF, the mechanism(s) responsible for the two disease entities are distinct. In MEN2B the p.Met918Thr variation occurs in exon 16 of RET in the tyrosine kinase domain which causes autophosphorylation and activation of RET. There is a significant amount of case-level data with the maximum points for genetic evidence reached (12 points). 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 carcinomas consistent with the disease multiple endocrine neoplasia type 2B. 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 IIA/2A (MIM:171400), (4)Pheochromocytoma (MIM:171300). These disease entities all follow an inheritance pattern of autosomal dominant. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we did find a difference in the molecular mechanism (defined above) and phenotypic expressivity between the disease entities MEN2A (MIM:171400) and MEN2B (162300), and therefore have split these curations. Therefore, the curation for RET-MEN2A can be found separately. In summary, RET is DEFINITIVELY associated with autosomal dominant multiple endocrine neoplasia type 2B. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.