CAM 256

Genetic Testing for Germline Mutations of the RET Proto-Oncogene

Category:Laboratory   Last Reviewed:January 2021
Department(s):Medical Affairs   Next Review:January 2022
Original Date:November 1997    

Description:
The rearranged during transfection (RET) proto-oncogene encodes a transmembrane receptor tyrosine kinase (Takahashi, Ritz, & Cooper, 1985) that regulates a complex network of signal transduction pathways during development, survival, proliferation, differentiation, and migration of the enteric nervous system progenitor cells (Hedayati, Zarif Yeganeh, Sheikholeslami, & Afsari, 2016). Disruption of RET signaling by mutation, gene rearrangement, overexpression or transcriptional up-regulation of the RET gene is implicated in several human cancers (Plaza-Menacho, Mologni, & McDonald, 2014), most commonly thyroid cancer, but also chronic myelomonocytic leukemia, acute myeloid leukemia, and lung, breast, pancreatic, and colon cancers (Gordon et al., 2018). Mutation of the RET gene in a germline cell results in an autosomal dominant hereditary cancer syndrome, multiple endocrine neoplasia type 2 (MEN2) characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and primary parathyroid hyperplasia (PPTH) (Figlioli, Landi, Romei, Elisei, & Gemignani, 2013).

This policy covers genetic testing for germline variants in the RET gene. For information on testing of tumors for RET variants in order to guide chemotherapy, see CAM 204115 Molecular Panel Testing of Cancers to Identify Targeted Therapy, CAM 20445 Testing for Targeted Therapy of Non-Small-Cell Lung Cancer, and CAM 20478 Molecular Markers in Fine Needle Aspirates of the Thyroid.

Regulatory Status
A search of the FDA database on 10/03/2020 using the term “genotyping” yielded 24 results. Additional tests may be considered laboratory developed tests (LDTs) if they are developed, validated and performed by individual laboratories. LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy:

  1. Genetic testing for RET proto-oncogene point mutations is considered MEDICALLY NECESSARY in any of the following situations:
    1. Individual is a member of a family with defined RET gene mutations
    2. Individual is a member of a family known to be affected by inherited medullary thyroid cancer, but not previously evaluated for RET mutations
    3. Individual with apparently sporadic medullary thyroid carcinoma (MTC)
    4. Individual is a first-degree relative of individuals with sporadic medullary thyroid cancer
    5. Individual with a diagnosis of MTC or clinical diagnosis of MEN2 (multiple endocrine neoplasia type 2) or primary C-cell hyperplasia

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Genetic testing for germline point mutations in the RET gene is considered NOT MEDICALLY NECESSARY in all other situations.

Rationale
The RET gene encodes a receptor tyrosine kinase that transduces growth and differentiation signals from the glial cell-derived neurotrophic factor family of ligands (Saarma, 2001). RET is expressed in the neuroendocrine parafollicular C-cells of the thyroid gland, adrenal medulla, neurons, and other tissues (Takaya et al., 1996). Unlike loss of function mutations that inactivate tumor suppressor proteins, oncogenic RET mutations result in a gain of function, inducing ligand-independent autophosphorylation of the RET receptor (Santoro et al., 1995), uncontrolled activation of MAPK and phosphoinositide 3-kinase pathways, and ultimately uncontrolled growth and cell dedifferentiation (Hansford & Mulligan, 2000; Raue & Frank-Raue, 2018).

Oncogenic activation of the RET gene can result from either somatic or germline alterations. Activating germline point mutations in RET with autosomal dominant heritability have been identified as the primary initiating events causative of malignancy in C-cells of the thyroid gland (MTC) and other clinical presentations of MEN2 (Hansford & Mulligan, 2000; Mulligan, 2014). These mutations are identified in 98-100% of MEN2 cases (Raue & Frank-Raue, 2018; Romei, Ciampi, & Elisei, 2016), which are responsible for 25% of MTC cases overall (Raue & Frank-Raue, 2015). An estimated 64,000 patients are diagnosed with thyroid cancer in the United States annually, and 1-2% of these cases are due to MTC. The most common alterations in the RET proto-oncogene are missense gain-of-function mutations mainly located in the extracellular domain of the RET gene (exons 10 or 11) and in the RET tyrosine kinase domain (exons 13, 14, 15 and 16) (ATA, 2016).

Germline RET mutations are associated with clear genotype-phenotype correlations (Plaza-Menacho et al., 2014). These clinical phenotypes can be divided into two subclasses of MEN2: multiple endocrine neoplasia type 2A (MEN2A) including familial medullary thyroid carcinoma (FMTC) and MEN type 2B (MEN2B) (Jasim et al., 2011). Over 100 RET point mutations, duplications, insertions, deletions, and fusions have been identified in patients with MEN2A, with the C634R mutation in exon 11 being the most common mutation, whereas only two RET mutations have been identified in patients with MEN2B (mainly M918T, and rarely A883F) (Giani et al., 2020; Romei et al., 2018). New variants continue to be reported (Paragliola et al., 2018; Qi et al., 2018). For example, in a case study of a 7-year-old girl in Italy, a “de novo” new germline RET deletion in exon 11 was found to cause features of both MEN2B without PHEO (pheochromocytoma), but “with a pelvic plexiform neurofibroma and with HPTH (primary hyperparathyroidism), which is typical of MEN2A” (Giani et al., 2020).

MEN2A is characterized by MTC and variable rates of PHEO, PPTH or both, with RET mutations in codons 609, 611, 618, or 620 of exon 10 and codon 634 of exon 11. Subtypes of classical MEN2A include development of cutaneous lichen amyloidosis and Hirschsprung disease. Absence of any clinical finding other than MTC in at least four family members is classified as FMTC (Wells et al., 2015).

MEN2B is characterized by highly aggressive MTC, usually PHEO, but not PPTH, and may exhibit musculoskeletal abnormalities and developmental defects with RET mutations in codons 918 and 883 of exon 15 (Wells et al., 2015). 

Table 1: Clinical expression of familial MTC-associated syndromes (Links, Verbeek, Hofstra, & Plukker, 2015).

 

FMTC (%)

MEN2A (%)

MEN2B (%)

MTC

100

100

100

Pheochromocytoma

0

10-60

50

Hyperparathyroidism

0

10-30

0

Marfanoid habitus

0

0

100

Intestinal ganglioneuromatosis

0

0

60-90

Mucosal neuromas

0

0

70-100

Clinical Validity
The development of tyrosine kinase inhibitors that specifically target RET (Suyama & Iwase, 2018) has allowed for genetic analysis of RET germline mutations to become the standard of care in the initial workup for detecting germline mutations and familial risk and identifying targeted therapy in MTC (Ernani, Kumar, Chen, & Owonikoko, 2016; Wells et al., 2015). Further, somatic RET rearrangements have recently been implicated in a variety of cancers, including chronic myelomonocytic leukemia; acute myeloid leukemia; and lung, breast, pancreatic, and colon cancers; a patient previously diagnosed with lung cancer underwent genomic profiling, and the identification of a RET point mutation associated with MTC allowed researchers to determine that this lung cancer diagnosis was incorrect (Gordon et al., 2018). A change in treatments proved to be very helpful for this patient. Other researchers have reported RET translocations in lung cancer cases, but they state that this is extremely rare (Zhao et al., 2016).

Guan et al. (2020) identified RET mutations in human epithelial ovarian cancer, providing another area of benefit from genetic testing of the RET gene for developing targeted therapies. Results showed that R693H and A750T mutants, in the juxtamembrane region and intracellular kinase domain, respectively, could promote the MAPK and AKT signaling pathway in ovarian cancer, and that the RET inhibitor vandetanib could decrease signal transduction and inhibit cancer growth (Guan et al., 2020).

Researchers have also found in two RET L790F index patients that somatic RET variants were not responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Normally, variations in MTC presentation could be attributed to RET germline variants (Mathiesen et al., 2020). However, Mathiesen et al. (2020) found an FLT3 R387Q variant - FLT3 being a protein commonly found in hematopoietic malignancies - that could have been a genetic modifier instead.

Clinical Utility
The strong genotype-phenotype correlation of RET mutations makes genetic screening of significant value in diagnosis, prognosis, and management of MEN2 (Eng et al., 1996; Frank-Raue, Rondot, & Raue, 2010; Romei et al., 2015) and resultant MTC (Machens, Lorenz, Weber, & Dralle, 2018), PHEO (Kimura, Takekoshi, & Naruse, 2018), and PPTH. Each specific RET mutation correlates with MEN2 presentation, age at onset of MTC, and MTC aggressiveness (Brandi et al., 2001). Screening and early treatment of the manifestations of MEN2 can prevent metastasis of MTC and the morbidity and mortality caused by PHEO (Gagel et al., 1988; Makri et al., 2018). Moreover, screening has been associated with improved survivorship and outcomes (Raue, Dralle, Machens, Bruckner, & Frank-Raue, 2018). Based upon these genotype-phenotype correlations, RET mutations have been stratified into three risk levels based on the penetrance and aggressiveness of the MTC (Brandi et al., 2001; Wells et al., 2015). Consequently, mutation type should guide major management decisions, such as whether and when to perform thyroidectomy (Machens, Elwerr, Lorenz, Weber, & Dralle, 2018; Machens, Lorenz, et al., 2018). Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life (Machens, Elwerr, et al., 2018; Machens, Lorenz, et al., 2018). Those with mutations in the high-risk category (codon 634 mutations) “should undergo thyroidectomy before reaching the age of 5 years” (Larouche, Akirov, Thomas, Krzyzanowska, & Ezzat, 2019). Annual biochemical screening in patients with a family history of FMTC or MEN2 can also be stopped in those patients who test negative for mutations (Wells et al., 2015).

Martins-Costa et al. (2018) performed RET genetic sequencing on exons 8, 10, 11, and 13-16 in 247 patients with MTC or who are at risk of developing MTC due to family history. Before genetic testing, 54 of these patients were diagnosed with sporadic disease and six were diagnosed with hereditary disease; after genetic testing, 31 patients were diagnosed with sporadic disease and 29 with hereditary disease (Martins-Costa et al., 2018). RET screening allowed several patients to be classified as hereditary who were initially diagnosed with sporadic MTC; 73 at-risk relatives were identified as mutation carriers, which will assist in long-term life and reproductive decisions (Martins-Costa et al., 2018).

A meta-analysis consisting of 438 Indian patients with MTC and 489 healthy controls of similar ages and genders was completed; all participants received molecular genetic testing including RET gene sequencing and SNP genotyping (Mishra, Kowtal, Rane, & Sarin, 2019). This study identified RET SNPs as a significant risk factor for developing hereditary MTC; CDKN2A and NAT2 SNPs with a significant risk of developing sporadic MTC (Mishra et al., 2019).

RET genetic screening was also provided to a total of 2,031 Italian subjects; this included 1,264 patients with sporadic MTC symptoms, 117 patients with hereditary MTC symptoms, and 650 relatives (Elisei et al., 2019). The researchers state, “A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1,264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found (Elisei et al., 2019).” This thereby underscores the significance of genetic screening in unsuspected MEN2 families. Sporadic MTC cases were present most commonly with a V804M mutation, and all M918T mutations were de novo “and exclusively associated with MEN2B” (Elisei et al., 2019). These researchers also identified several variants of unknown significance (VUS).

RET genetic screening could also disclose new variants with their respective phenotypes. Yang et al. (2020) described a compound C634Y/V292M transmutation in a northern Chinese family that was associated with a more aggressive clinical presentation. Carriers of this variant had bilateral MTC with PHEO or lymph node metastasis with faster cell growth (cell growth speed identified in vitro). On the other hand, carriers of the V292M variant were asymptomatic, and carriers of the C634Y mutation only had elevated calcitonin (Yang et al., 2020). This has demonstrated the striking variability in MTC clinical presentation based on RET gene variants, making it critical to aid in any future potential treatment regimen.

European Society for Medical Oncology (ESMO) (Filetti et al., 2019, 2020)
The ESMO has published clinical practice guidelines on diagnosis, treatment, and follow-up of thyroid cancer, stating that “All patients with MTC should be offered genetic counselling and screened for germline RET mutations” (Filetti et al., 2020). Filetti et al. (2020) also stated that “screening for somatic RET mutations is only recommended if RET inhibitor therapy is planned.”

American Thyroid Association (ATA) (Wells et al., 2015)
The ATA published revised guidelines (Wells et al., 2015) which state that:

  • “Initial testing for patients with MEN2A phenotype is either a single or multi-tiered analysis to detect RET mutations in exon 10 (codons 609, 611, 618, and 620), exon 11 (codons 630 and 634), and exons 8, 13, 14, 15, and 16. Grade B Recommendation”
  • Initial testing for patients with MEN2B phenotype should be tested for the RET codon M918T mutation (exon 16), and if negative, the RET codon A883F mutation (exon 15).
  • “Sequencing of the entire coding region should be reserved for situations in which no RET mutation is identified or there is a discrepancy between the MEN2 phenotype and the expected genotype. Grade B Recommendation
  • Patients with the MEN2B phenotype should be tested for the RET codon M918T mutation (exon 16), and if negative, the RET codon A883F mutation (exon 15). If there are no mutations identified in these two exons the entire RET coding region should be sequenced. Grade B Recommendation
  • Patients with presumed sporadic MTC should have genetic testing to detect a germline RET mutation. If a RET mutation is found the patient should have genetic testing. Grade B Recommendation
  • In very rare families who meet the clinical criteria for MEN2A or 2B, despite negative sequencing of the entire RET coding region, the relatives at risk should be periodically screened by conventional methods for MTC, PHEO, and HPTH. After the initial evaluation, screening should continue at 1- to 3-year intervals. Grade C Recommendation
  • Genetic counseling and genetic testing for RET germline mutations should be offered to
    • First-degree relatives of patients with proven hereditary MTC,
    • Parents whose infants or young children have the classic phenotype of MEN2B,
    • Patients with CLA [cutaneous lichen amyloidosis], and
    • Infants or young children with HD and exon 10 RET germline mutations, and adults with MEN2A and exon 10 mutations who have symptoms suggestive of HD” (Wells et al., 2015)

National Comprehensive Cancer Network (NCCN, 2020a, 2020b)
NCCN guidelines for neuroendocrine and adrenal tumors (NCCN, 2020a) recommends that for diagnosis of or clinical suspicion of MEN2, genetic counseling and RET genetic testing should be offered to:

  • “An individual with a diagnosis of MTC or clinical diagnosis of MEN2 or primary C-cell hyperplasia;
  • An at-risk relative of an individual with a known germline RET mutation.
    • Genetic testing of at-risk family members at a very early age”
  • “50% of cases have de novo RET mutations; therefore, even if a family history is not suggestive of a hereditary syndrome, genetic testing for RET mutations should still be performed on the affected individual
  • All patients with MTC should be tested for germline mutation of the RET oncogene even if the family history is not suggestive of a hereditary syndrome, because about 50% of patients with presumed sporadic MTC have a de novo germline mutation” (NCCN, 2020a)

NCCN Guidelines for Thyroid Carcinoma (NCCN, 2020b) stated the following:

  • Medullary thyroid carcinoma on fine needle aspiration (FNA) should be screened for RET proto-oncogene mutations (exons, 10,11,13-16)
  • Medullary thyroid carcinoma diagnosed after initial thyroid surgery should be screened for germline RET proto-oncogene mutations (exons 10, 11, 13-16) with genetic counseling
  • “Genetic testing for RET proto-oncogene mutations is recommended for all patients with newly diagnosed clinically apparent sporadic MTC, and for screening children and adults in known kindreds with inherited forms of MTC; genetic counseling should be considered” (NCCN, 2020b)

The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) (Lindeman et al., 2018)
The 2013 guidelines from CAP, IASLC and AMP for molecular testing in lung cancer patients have been updated in 2018; new recommendations state that RET testing is approved in lung cancer specimens “as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative” because “RET molecular testing is not recommended as a routine stand-alone assay outside the context of a clinical trial” (Lindeman et al., 2018).

The British Thyroid Association (BTA, 2014)
The BTA has stated, in regards to MTC, that “In all confirmed cased of MTC, RET mutation analysis to establish the possible genetic basis for the disease within an individual or kindred, should be performed even in the absence of a positive family history (BTA, 2014).” 

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  43. Santoro, M., Carlomagno, F., Romano, A., Bottaro, D. P., Dathan, N. A., Grieco, M., . . . et al. (1995). Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science, 267(5196), 381-383. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/7824936
  44. Suyama, K., & Iwase, H. (2018). Lenvatinib: A Promising Molecular Targeted Agent for Multiple Cancers. Cancer Control, 25(1), 1073274818789361. doi:10.1177/1073274818789361
  45. Takahashi, M., Ritz, J., & Cooper, G. M. (1985). Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell, 42(2), 581-588. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/2992805
  46. Takaya, K., Yoshimasa, T., Arai, H., Tamura, N., Miyamoto, Y., Itoh, H., & Nakao, K. (1996). Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med (Berl), 74(10), 617-621. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/8912182
  47. Wells, S. A., Jr., Asa, S. L., Dralle, H., Elisei, R., Evans, D. B., Gagel, R. F., . . . American Thyroid Association Guidelines Task Force on Medullary Thyroid, C. (2015). Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 25(6), 567-610. doi:10.1089/thy.2014.0335
  48. Wells, S. A., Jr., Pacini, F., Robinson, B. G., & Santoro, M. (2013). Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab, 98(8), 3149-3164. doi:10.1210/jc.2013-1204
  49. Yang, Z., Qi, X., Gross, N., Kou, X., Bai, Y., Feng, Y., . . . Huang, Z. (2020). The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A. J Cell Mol Med. doi:10.1111/jcmm.15922
  50. Zhao, W., Choi, Y. L., Song, J. Y., Zhu, Y., Xu, Q., Zhang, F., . . . Mao, M. (2016). ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare. Lung Cancer, 94, 22-27. doi:10.1016/j.lungcan.2016.01.011

Coding Section

Codes Number Description
CPT  81404 

Molecular pathology procedure, Level 5

Gene:

RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F)
  81405

Molecular pathology procedure, Level 6

Gene:

RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2A and familial medullary thyroid carcinoma), targeted sequence analysis (eg, exons 10, 11, 13-16) 
  81406 

Molecular pathology procedure, Level 7

Gene:

MUTYH (mutY homolog [E.coli]) (eg, MYH-associated polyposis), full gene sequence 
HCPCS  S3840 DNA analysis for germline mutations of the ret proto-oncogene for susceptibility to multiple endocrine neoplasia type 2
ICD-10-CM (effective 10/01/15)  C73  Malignant neoplasm of thyroid gland 
  C7989  Secondary malignant neoplasm of other specified sites  
  D093  Carcinoma in situ of Thyroid and other Endocrine Glands 
  D098  Carcinoma in situ of other specified sites 
  Z85850  Personal history of malignant neoplasm of Thyroid 
  Z808  Family History of Malignant neoplasm of other organs or systems 
ICD-10-PCS (effective 10/01/15)   

 ICD-10 codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure. 

     

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2013 Forward      

01/13/2021 

Annual review, reformatting for clarity, updating policy number. Adding verbiage regarding testing for a diagnosis of MTC. Also updating description, rationale and references. 

01/01/2020 

Annual review, no change to policy intent. 

01/09/2019 

Annual review, updating title for specificity and adding coverage criteria for individuals with a clinical diagnosis of MEN2. 

01/17/2018 

Annual review, no change to policy intent. 

04/26/2017 

Interim review to align with Avalon quarterly schedule. Updated category to Laboratory. 

12/29/2016 

Annual review. No changes made to policy. 

04/27/2016 

Interim review to add verbiage #5 in the policy. 

01/04/2016 

Updated CPT codes. no change to intent of policy. 

12/14/2015 

Interim review, adding policy language to allow coverage for "individual with apparently sporadic medullary cancer". 

11/04/2015 

Annual review, no change to policy intent. Added ICD 10 coding. 

11/06/2014 

Annual review, no change to policy intent. Added guidelines and coding. 

11/04/2013

Added Benefit Application and Rationale


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