RET Y791F - GET-Evidence



(RET Tyr791Phe)

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Edited in this revision:

Short summary

Several publications asserted this variant caused familial medullary thyroid cancer in a dominant manner. However, a 2010 publication by Erlic et al. examined a larger set of controls, finding the variant no more common in cases than it was in controls. These authors conclude that the variant is not a serious cause of the disease, although they could not rule out a small effect on risk.

Variant evidence
Computational 1

Other variants in this gene associated with this disease

Functional -

Erlic et al observations contradict a high penetrance “Mendelian” effect. No evidence supporting other effects.

See Erlic Z et al. 2010 (19906784).

Familial -
Clinical importance
Severity 3
Treatability 4

If this variant affects susceptibility to this cancer (and no data has been reported to support this), the effect would be fairly modest. In addition, the disease itself is fairly rare, with a lifetime risk of 0.05%.



Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr10:43613908: 0.1% (14/10758) in EVS
  • Frequency shown in summary reports: 0.1% (14/10758)


Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Höppner W. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998 Mar;83(3):770-4. PubMed PMID: 9506724.


Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peçzkowska M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 May 9;346(19):1459-66. PubMed PMID: 12000816.


Fitze G, Schierz M, Bredow J, Saeger HD, Roesner D, Schackert HK. Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations. Ann Surg. 2002 Nov;236(5):570-5. PubMed PMID: 12409662; PubMed Central PMCID: PMC1422614.


Jindrichová S, Vcelák J, Vlcek P, Neradilová M, Nemec J, Bendlová B. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004 Nov;183(2):257-65. PubMed PMID: 15531714.


Frank-Raue K, Rondot S, Hoeppner W, Goretzki P, Raue F, Meng W. Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2005 Jul;90(7):4063-7. Epub 2005 May 3. Erratum in: J Clin Endocrinol Metab. 2005 Oct;90(10):5575. PubMed PMID: 15870131.


Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, Waldhäusl W, Vierhapper H. Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? J Clin Endocrinol Metab. 2005 Nov;90(11):6232-6. Epub 2005 Aug 23. PubMed PMID: 16118333.


Dvorakova S, Vaclavikova E, Ryska A, Cap J, Vlcek P, Duskova J, Kodetova D, Holub V, Novak Z, Bendlova B. Double germline mutations in the RET Proto-oncogene in MEN 2A and MEN 2B kindreds. Exp Clin Endocrinol Diabetes. 2006 Apr;114(4):192-6. PubMed PMID: 16705552.


Vaclavikova E, Dvorakova S, Sykorova V, Bilek R, Dvorakova K, Vlcek P, Skaba R, Zelinka T, Bendlova B. RET mutation Tyr791Phe: the genetic cause of different diseases derived from neural crest. Endocrine. 2009 Dec;36(3):419-24. doi: 10.1007/s12020-009-9242-7. Epub 2009 Oct 14. PubMed PMID: 19826964.

Molecular genetic analysis was performed in 276 families with medullary thyroid carcinoma (31 familial and 245 apparently sporadic), 29 patients with apparently sporadic pheochromocytoma, and 122 families with Hirschsprung’s disease (a total of 427 families and unrelated individuals). The RET Y791F variant was found in 31 patients from 10 families — an allele frequency of 1.2% in these cases. The authors do not list any controls to compare this to.

The authors observe high variability in type of disease and age of onset; while most cases are summarized as late onset and high cure rates, the authors report two patients carrying this variant with aggressive tumors. The authors conclude: “Despite the fact that the mutation was categorized as the least-high risk mutation, we tend to agree with recommendation to perform prophylactic total thyroidectomy in all carriers of the mutation regardless of calcitonin levels, ideally before 10 years of age.”

Erlic Z, Hoffmann MM, Sullivan M, Franke G, Peczkowska M, Harsch I, Schott M, Gabbert HE, Valimäki M, Preuss SF, Hasse-Lazar K, Waligorski D, Robledo M, Januszewicz A, Eng C, Neumann HP. Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2010 Jan;95(1):308-13. doi: 10.1210/jc.2009-1728. Epub 2009 Nov 11. PubMed PMID: 19906784; PubMed Central PMCID: PMC2805484.

These authors perform a more extensive survey of controls in addition to examining cases and report this variant in 8 out of 1000 controls (0.8%) and in 13 out of 1475 patients in the European-American Pheochromocytoma-Paraganglioma registry. An additional four(?) relatives of these patients were discovered also to be carriers. 15 of these patients and relatives carrying Y791F were re-evaluated and found to have no family history or additional MEN 2 features.

The authors observe that prior reports had smaller (or lacked) control populations, sporadic cases and a lack of familial evidence. They also observe the variant does not segregate with the disease in their study.

The authors conclude that, in contrast to its prior treatment, this variant is not a Mendelian mutation responsible for MEN 2.


Other external references

  • GeneTests records for the RET gene
    Hirschsprung Disease
    Multiple Endocrine Neoplasia Type 2
    RET-Related Hirschsprung Disease
  • Score: 0.402 (possibly damaging)
    Web search results (579 hits -- see all)
  • JCEM -- eLetters for Erlic et al., 95 (1) 308-313
    Pathogenicity of the p.Tyr791Phe RET Germline Mutation. Andreas Machens, Henning Dralle ... 2007 Y791F RET mutation and early onset of medullary thyroid ...
  • New Products / Carna Biosciences Inc.
    RET[G691S] (Custom Profiling Comparative Inhibitory Activity) RET[G691S] (Custom ... RET[Y791F] (Custom Profiling Comparative Inhibitory Activity) ...
  • Primary hyperparathyroidism as the leading symptom in a ...
    Primary hyperparathyroidism as the leading symptom in a patient with a Y791F RET mutation. ... a mutation (Y791F, TAT-->TTT) in exon 13 of the RET proto-oncogene. ...
  • CORDIS: Technology Marketplace: Results
    Abstract: The proto-oncogene RET a member of the tyrosine-kinase receptor its ... The RET Y791F mutation may be a common genetic abnormality underlying ...
  • Fenotypes in patients with Y791F mutation of RET protooncogene
    Mutation Y791F of RET protooncogene is a well known mutation so far described in families with FMTC and familial pheochromocytoma in one family. ...
  • RET-Familial Medullary Thyroid Carcinoma Mutants Y791F and ...
    The RET proto-oncogene encodes a receptor tyrosine kinase. whose dysfunction plays a ... properties of two FMTC-associated RET mutations, Y791F and ...
  • RET-Familial Medullary Thyroid Carcinoma Mutants Y791F and ...
    RET-Familial Medullary Thyroid Carcinoma Mutants Y791F and S891A Activate a Src/JAK/STAT3 Pathway, Independent of Glial Cell Line–Derived Neurotrophic Factor ...
  • High Penetrance of Pheochromocytoma Associated with the Novel ...
    Patients: Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. ...
  • Transcriptome analysis in mouse tumors induced by Ret-MEN2 ...
    Activating mutations in the Ret proto-oncogene are responsible for occurrence of multiple ... NIH-RET(MEN2B) (A883F, M918T) and NIH-RET(FMTC) (Y791F)-specific ...
  • Carna Biosciences, Inc.

Other in silico analyses

  • NBLOSUM100 score = –4
  • GET-Evidence autoscore = 5

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