Inheritance

Autosomal dominant

Prevalence

 1:35,000

Source: GeneReviews

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Hereditary Cancer GCEP, accessed 06.23.2023

Clinical Validity Scoring Notes and points

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.

Clinical Validity Points Total

18

Source: ClinGen Hereditary Cancer GCEP, accessed 06.23.2023

Clinical Validity Classification

Definitive

Source: ClinGen Hereditary Cancer GCEP, accessed 06.23.2023

Molecular Mechanism

Gain of function

NOTE: MEN2B is also caused by GOF, but the GCEP states this is a different GOF mechanism.

Source: ClinGen Hereditary Cancer GCEP, accessed 06.23.2023

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

Gene SOPs & Notes

Different RET variants confer different cancer risks (for MEN2A, MEN2B, which is curated separately, and FMTC). Ensure the variant and gene description are specific to the variant identified.

Curation Summary:

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 06.23.2023 https://broadinstitute.atlassian.net/browse/CIT-130

Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

 Hereditary Cancer GCEP, accessed 06.23.2023

Clinical Validity Scoring Notes and points

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.

Clinical Validity Points Total

 17

Clinical Validity Classification

DEFINITIVE 

Source:  Hereditary Cancer GCEP, accessed 06.23.2023

Molecular Mechanism

Gain of function

(PLEASE NOTE: the mechanism for MEN2A is also GOF, but the mechanism is distinct per the Hereditary Cancer GCEPs curation.)  

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary:

Case ID, Curator name, Date, Jira ticket link