• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The RET gene is associated with autosomal dominant multiple endocrine neoplasia type 2 (MEN2) syndrome (MedGen UID: 9958) and nonsyndromic Hirschsprung disease (MedGen UID: 419188).

The RET gene encodes the protein RET proto-oncogene, a receptor tyrosine kinase required for the development of neural crest-derived cells and the urogenital system, as well as the central and peripheral nervous systems, notably the enteric nervous system. As a plasma membrane signal transducer, RET is involved in numerous cellular processes, including cellular proliferation, adhesion and migration, and differentiation.

RET Heterozygote
MedGen UID: 441301

Clinical condition
Multiple endocrine neoplasia type 2 (MEN2) is a tumor-predisposition syndrome that results from pathogenic variants in the RET gene. MEN2 is divided into three subtypes: type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). The characteristic signs, symptoms, and risks of specific tumors differ between these subtypes. The most common sign of MEN2 is medullary thyroid carcinoma (MTC). An estimated 25% of MTC cases are the result of germline mutations in the RET gene. Some affected individuals can also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure.

MEN2A makes up approximately 70–80% of MEN2 cases and is clinically diagnosed by the occurrence of two or more specific endocrine tumors (medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma, or parathyroid hyperplasia) in a single individual (PMID: 21552134). Typically, MTC presents prior to age 35 (PMID: 11739416, 20301434, 21552134). Pheochromocytomas usually present either after MTC or concomitantly (PMID: 21552134). Pheochromocytomas in individuals with MEN2A are typically diagnosed at an earlier age, have more subtle symptoms, and are more likely to be bilateral than sporadic tumors (PMID: 21552134). Malignant transformation occurs in approximately 4% of cases (PMID: 7595173). Hyperparathyroidism, another symptom of MEN2A, is typically mild and may cause no symptoms; however, hypercalciuria and renal calculi may occur. The average age of onset is 38 (PMID: 11739416, 20301434).

MEN2B accounts for 5% of MEN2 cases (PMID: 21552134). MEN2B is characterized by medullary thyroid carcinoma in nearly all affected individuals, mucosal neuromas of the lips and tongue, pheochromocytoma (50%), intestinal ganglioneuromas, and a Marfanoid body habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat (PMID: 21552134). Individuals who do not undergo thyroidectomy at an early age are likely to develop metastatic MTC (PMID: 11739416, 20301434, 21552134).

FMTC is characterized by MTC in the absence of pheochromocytoma, parathyroid adenoma, and hyperplasia (PMID: 21552134). FMTC constitutes approximately 10–20% of MEN2 cases (PMID: 21552134). The age of onset is typically later and the penetrance lower than what is observed in MEN2A and MEN2B (PMID: 21552134). All family members with FMTC should have an adequate medical history that demonstrates the absence of pheochromocytoma or hyperparathyroidism (PMID: 11739416, 20301434, 25810047). FMTC is typically viewed as a variant of MEN 2A with decreased penetrance of pheochromocytoma and HPT, rather than a distinct subtype (PMID: 21552134).

Hirschsprung’s disease, a congenital condition characterized by aganglionosis of the gut, is also associated with pathogenic variants in RET. Up to 50% of those with familial Hirschsprung’s disease and 15–20% of simplex cases have a germline mutation in RET. Approximately 7% of individuals with MEN2A also have Hirschsprung’s disease. Loss of function mutations throughout the RET gene may cause Hirschsprung’s disease, while pathogenic variants in exon 10 of RET are associated with both MEN2A and Hirschsprung’s disease (PMID: 25810047, 20301434).

A summary of MEN2 subtypes and the associated risks are in the table below (PMID: 20301434):

SubtypeMTC RiskPheochromocytoma RiskHyperparathyroidism Risk
FMTC~100%- -

Gene information
RET is a proto-oncogene and member of the cadherin superfamily. This gene plays a crucial role in neural crest development (NCBI Gene. Gene ID: 5979. Accessed April 13, 2016). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

Multiple endocrine neoplasia type 2 (including MEN2A, MEN2B, and FMTC) has autosomal dominant inheritance. This means that an individual with a pathogenic variant in the RET gene has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. The rate of spontaneous de novo mutations for MEN2A is approximately 5%; for MEN2B, it is approximately 50% (PMID: 20301434).

The following recommendations are suggested for establishing the extent of disease in and the needs of an individual diagnosed with MEN2 (PMID: 11739416, 25810047, 17453286, 20301434, National Comprehensive Cancer Network. Guidelines for the treatment of thyroid carcinoma. Version 2.2015):

  • referral to an endocrinologist
  • a consultation with a medical geneticist and/or genetic counselor
  • biochemical evaluations
    • plasma calcitonin
    • plasma catecholamines and metanephrines
    • serum calcium and parathyroid hormone
  • a workup to evaluate for metastatic disease in individuals with MTC
    • CT with contrast for chest and abdomen
    • MRI of liver with nodal disease or calcitonin >400 pg/mL

Prophylactic thyroidectomy: Prophylactic thyroidectomy is recommended for all individuals with MEN2; however, the timing of surgery varies and is suggested based on the underlying RET pathogenic present in an individual. The American Thyroid Association (ATA) has proposed guidelines for the management of MTC and pheochromocytoma screening based on the specific variant present in an individual with MEN2 (PMID: 25810047). These guidelines are summarized below:

ATA-Highest Risk: Those with MEN2B and the M918T variant are at a significantly elevated risk of developing medullary thyroid cancer in the first few years of life, so in these cases, total thyroidectomy is recommended within the first year or even the first few months of life. Level VI lymph node dissection is dependent on the ability to identify, preserve, or transplant the parathyroid glands. Physical exam, cervical ultrasound, serum calcitonin, and carcinoembryonic antigen are recommended every 6 months for the first postoperative year, then annually thereafter (PMID: 25810047).

ATA-High Risk: Those with the A883F variant and pathogenic variants within codon 634 of the RET variant are at a high risk of developing medullary thyroid cancer. In these cases, annual physical examination, cervical ultrasound, and measurement of serum calcitonin levels should begin at 3 years of age. Total thyroidectomy is recommended at or before 5 years of age, depending upon serum calcitonin results (PMID: 25810047).

ATA-Moderate Risk: Those with the following pathogenic variants in RET are at moderate risk of developing medullary thyroid cancer: G533C, C609F/G/R/S/Y, C611F/G/S/Y/W, C618F/R/S, C620F/R/S, C630R/Y, D631Y, K666E, E768D, L790F, V804L, V804M, S891A, and R912P. In these cases, total thyroidectomy is recommended when serum calcitonin levels become elevated, or in childhood if parents do not wish to embark on a lengthy period of surveillance (PMID: 25810047).

For all individuals with a pathogenic RET variant who have not had a thyroidectomy, annual biochemical screening is recommended, with immediate thyroidectomy if results are abnormal.
Annual serum calcitonin screening should begin at age 6 months for children with MEN2B and at age 3–5 years for children with MEN2A or FMTC (National Comprehensive Cancer Network. Guidelines for the treatment of thyroid carcinoma. Version 2.2015)).

Pheochromocytoma screening: Prior to any surgery, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening in any individual with MEN2A or MEN2B. In a prospective study of at-risk family members with a RET mutation, 8% had pheochromocytoma detected at the same time as MTC. For individuals whose initial screening results are negative for pheochromocytoma, annual biochemical screening is recommended, followed by MRI or CT if the biochemical results are abnormal.

Screening for pheochromocytoma is recommended to begin at age 11 for those in the ATA-Highest Risk and High risk categories and at age 16 for those in the ATA-Moderate risk category (PMID: 25810047). Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy—or as early as possible during an unplanned pregnancy. Dopamine D2 receptor antagonists (e.g. metoclopramide and veralipride) and β-blockers have a high potential to cause an adverse reaction in individuals with pheochromocytoma and should therefore be avoided (PMID: 11739416, 25810047, 17453286, 20301434, National Comprehensive Cancer Network. Guidelines for the treatment of thyroid carcinoma. Version 2.2015).

Parathyroid Surveillance: Surveillance for parathyroid adenoma or hyperplasia, including annual biochemical screening, is recommended for affected individuals who have not had parathyroidectomy and parathyroid autotransplantation. Parathyroid adenoma or hyperplasia diagnosed at the time of thyroidectomy is treated with either resection, subtotal parathyroidectomy, or total parathyroidectomy. In most individuals with MEN2A, hyperparathyroidism may be diagnosed many years after thyroidectomy (PMID: 11739416, 25810047, 17453286, 20301434, National Comprehensive Cancer Network. Guidelines for the treatment of thyroid carcinoma. Version 2.2015)).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant is present in the RET gene is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding RET are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review Date: April 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
RET NM_020975.4