RET -- Familial Medullary Thyroid Cancer
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:9967
Inherited medullary thyroid carcinoma (MTC) is primarily caused by RET mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the RET proto-oncogene .....novel germline RET S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations.
Qi et al, 2019, PMID: 31364476
More than 90% of the cases of MEN 2A and FMTC are caused by mutations in one of the six highly conserved cysteine residues that are encoded by exons 10 (codons 609, 611,618, and 620) and 11 (codons 630 and 634) of the RET gene. In a few MEN 2A or FMTC families, mutations have been reported involving non-cysteine domains in exons 11 (codon 631), 13(codons 768, 790, and 791), 14 (codon 804 and844), 15 (codon 891), or a 9-bp duplication in exon 8 (8--12) ....Codon 804 mutations of the RET exon 14,which have been detected in a few MEN 2A orFMTC families, include single-base substitutionsresulting in a GTG !TTG (V804L), GTG!CTG(V804L), or GTG!ATG (V804M) missensechange (11, 15--21). It has been assumed that mutation in non-cysteine domains, including codon 804 in exon 14, results in a weaker onco-genic activation of the RET protein and an attenuated form of the MEN 2A or FMTC phenotype compared to that observed in patientswith cysteine domain mutation at codon 634 ofexon 11 (20, 22, 23). This proposal is supportedby clinical observations showing a late onset andpossibly a reduced penetrance and expression ofthe disease phenotype in families with codon 804mutations of the RET exon 14 (11, 20)
Patocs et al, 2003, PMID: 12694233
Pilot application of harmonised terms:
Inheritance:
Autosomal Dominant
Optional modifier -- incomplete penetrance
Allelic requirement:
Monoallelic_aut
Disease associated variant consequences:
Altered protein product
Narrative summary of molecular mechanisms:
The molecular mechanism of disease in MEN2a (including the isolated familial medullary thyroid cancer) is gain of function, resulting from an activating missense germline mutation of the RET proto-oncogene (a tyrosine kinase). Most MEN2A/FMTC cases result from missense mutations that lead to ligand-independent dimerization (constitutive activation), located in one of six cysteine codons in the extracellular domain of the encoded protein (codons 609, 611, 618, and 620 in exon 10 and codons 630 and 634 in exon 11. In a few families a small in frame duplication and small 2bp indel have been found. Attenuated phenotypes may be associated with cysteine domain mutations at codon 634 of exon 11 and at non-cysteine residues (including codon 804 in exon 14)
List variant classes in this gene proven to cause this disease:
Missense
Inframe_deletion
Inframe_insertion
Potential novel variant classes based on predicted functional consequence
splice_acceptor_variant predicted to escape NMD
splice_donor_variant predicted to escape NMD
frameshift_variant predicted to escape NMD
stop_gained predicted to escape NMD
Stop lost
Not included
splice_region_variant
splice_acceptor_variant
(splice_acceptor_variant predicted to undergo NMD)
splice_donor_variant
(splice_donor_variant predicted to undergo NMD)
Frameshift_variant
(frameshift_variant predicted to undergo NMD)
Stop_gained
(stop_gained predicted to undergo NMD)
start_lost
5_prime_UTR_variant
3_prime_UTR_variant
(gain of upstream Start [uORF])
(gain of upstream Start [oORF])
(Stop lost [uORF])
(Stop lost [oORF])
(Start lost [uORF])
(Frameshift [uORF])
(Frameshift [oORF])
(Stop gained [uORF])