Familial medullary thyroid carcinoma: genes and variants
Familial medullary thyroid carcinoma is linked to 2 analyzed proteins (RET and NTRK1). 13 DNA variants are known to cause it; 119 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Familial medullary thyroid carcinoma
RET: Proto-oncogene tyrosine-protein kinase receptor Ret
Its activation by GDNF-family ligands guides development of the enteric nervous system, kidney, and other tissues. Activating variants cause multiple endocrine neoplasia type 2 and can drive cancer, whereas loss-of-function variants are an important cause of Hirschsprung disease.
13 disease-causing and 106 uncertain variants in RET are linked to Familial medullary thyroid carcinoma.
NTRK1: High affinity nerve growth factor receptor
Nerve-growth-factor signaling through this pathway supports survival and differentiation of sensory and sympathetic neurons. Loss-of-function variants cause congenital insensitivity to pain with anhidrosis, whereas oncogenic NTRK1 fusions can drive diverse cancers.
0 disease-causing and 13 uncertain variants in NTRK1 are linked to Familial medullary thyroid carcinoma.
Where Familial medullary thyroid carcinoma variants cluster
- RET Protein kinase (positions 724–1016): 6 of 13 disease-causing changes, 1.8× more than its size predicts.
Known disease-causing variants in Familial medullary thyroid carcinoma
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| RET C618G | 618 | Extracellular | Disease-causing (★★) |
| RET V804M | 804 | Protein kinase | Disease-causing (★★) |
| RET V804L | 804 | Protein kinase | Disease-causing (★★) |
| RET S891A | 891 | Protein kinase | Disease-causing (★★) |
| RET C634Y | 634 | Extracellular | Disease-causing (★★) |
| RET L790F | 790 | Protein kinase | Disease-causing (★★) |
| RET K424N | 424 | Cadherin-like region 4 (CLD4) | Disease-causing (★★) |
| RET F555C | 555 | Extracellular | Disease-causing (★★) |
| RET C620Y | 620 | Extracellular | Disease-causing (★★) |
| RET K666N | 666 | Cytoplasmic | Disease-causing (★★) |
| RET S891L | 891 | Protein kinase | Disease-causing (★) |
| RET S649L | 649 | Transmembrane | Disease-causing (★) |
| RET R972G | 972 | Protein kinase | Disease-causing (★) |
Which prediction tools work for Familial medullary thyroid carcinoma
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 93 out of 100
- PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 92 out of 100
- phyloP: 70 out of 100
Same protein, different disease
- Multiple endocrine neoplasia is also caused by RET variants; they fall mostly in different places as the Familial medullary thyroid carcinoma variants (53 disease-causing).
- Hirschsprung disease is also caused by RET variants; they fall mostly in different places as the Familial medullary thyroid carcinoma variants (16 disease-causing).
- MEN2 phenotype: Unclassified is also caused by RET variants; they fall partly in the same places as the Familial medullary thyroid carcinoma variants (5 disease-causing).
Diseases related to Familial medullary thyroid carcinoma
- Ovarian cancer, also linked to NTRK1 and RET
- Colorectal cancer, also linked to NTRK1 and RET
- Non-small cell lung carcinoma, also linked to NTRK1 and RET
- Charcot-Marie-Tooth disease, also linked to NTRK1
- Multiple endocrine neoplasia, also linked to RET
- Gastrointestinal stromal tumor, also linked to RET
- Pheochromocytoma, also linked to RET
- Hereditary insensitivity to pain with anhidrosis, also linked to NTRK1
- Hirschsprung disease, also linked to RET
- Hepatocellular carcinoma, also linked to RET
- Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, also linked to RET
- MEN2 phenotype: Unclassified, also linked to RET
Frequently asked questions
Which genes are linked to Familial medullary thyroid carcinoma?
In CATVariant, Familial medullary thyroid carcinoma is linked to 2 analyzed proteins: RET (Proto-oncogene tyrosine-protein kinase receptor Ret) and NTRK1 (High affinity nerve growth factor receptor).
How many genetic variants are linked to Familial medullary thyroid carcinoma?
138 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 119 are of uncertain significance or have conflicting reports.
Which uncertain variants in Familial medullary thyroid carcinoma look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
Which variant effect predictor works best for Familial medullary thyroid carcinoma?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 8 disease-causing and 41 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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