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Genetic Testing for RET Proto-Oncogene Germline Mutations
Last Review Date: November 11, 2016
Number: MG.MM.DM.LA.17aCv3
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Definition
RET proto-oncogene
Medullary thyroid cancer
Multiple endocrine neoplasia
Type 2 (MEN2)
Pheochromocytoma
The only gene known to be associated MEN Type 2, it is divided into three
subtypes: MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC).
A malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid
that occurs sporadically or as a component of multiple endocrine neoplasia (MEN)
Type 2.
A hereditary disorder which manifests as medullary thyroid carcinoma, hyperparathyroidism and phaechromocytoma, is caused by mutations in the RET protooncogene.
A neuroendocrine tumor of the adrenal medulla (arising from the chromaffin cells)
glands which is usually benign: 50% with MEN2A affected.
Guideline
Genetic testing for RET proto-oncogene point mutations to assess multiple endocrine neoplasia type 2
(MEN2) or medullary thyroid cancer risk is considered medically necessary when the results of testing
will directly impact treatment any of the following criteria are met:
1. Member’s family harbor defined RET mutations
2. Member’s family has a history of inherited MTC or pheochromocytoma, but presence of RET
gene mutation is unknown
3. Member’s has a 1st degree relative with MTC and germline RET mutations
4. Member’s has sporadic MTC
Limitations/Exclusions
Genetic testing is not considered medically necessary for genes additional to the RET.
Genetic Testing for Testing for RET Proto-Oncogene Germline Mutations
Last review: November 11, 2016
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Revision History
1/8/2016: Title changed from Genetic Testing for Medullary Thyroid Carcinoma to Genetic Testing for RET ProtoOncogene Germline Mutations and Definition section enhanced.
Applicable Procedure Codes
81404
Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation
scanning or duplication/deletion variants of 6-10 exons
81405
Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation
scanning or duplication/deletion variants of 11-25 exons
81406
Molecular pathology procedure Level 7
88271
Molecular cytogenetics; DNA probe, each (eg, FISH)
Applicable ICD-10 Diagnosis Codes
C73
Malignant neoplasm of thyroid gland
C74.00
Malignant neoplasm of cortex of unspecified adrenal gland
C74.01
Malignant neoplasm of cortex of right adrenal gland
C74.02
Malignant neoplasm of cortex of left adrenal gland
C74.10
Malignant neoplasm of medulla of unspecified adrenal gland
C74.11
Malignant neoplasm of medulla of right adrenal gland
C74.12
Malignant neoplasm of medulla of left adrenal gland
C74.90
Malignant neoplasm of unspecified part of unspecified adrenal gland
C74.91
Malignant neoplasm of unspecified part of right adrenal gland
C74.92
Malignant neoplasm of unspecified part of left adrenal gland
C75.0
Malignant neoplasm of parathyroid gland
E31.22
Multiple endocrine neoplasia [MEN] type IIA
E31.23
Multiple endocrine neoplasia [MEN] type IIB
Z83.41
Family history of multiple endocrine neoplasia [MEN] syndrome
Genetic Testing for Testing for RET Proto-Oncogene Germline Mutations
Last review: November 11, 2016
Page 3 of 3
References
1.
Online Mendelian Inheritance in Man® (OMIM) Database. 2015. http://omim.org/entry/155240. Accessed June
30, 2015.
2.
Carson EB, McMahon M, Baylin SB, Nelkin BD. Ret gene silencing is associated with Raf-1-induced medullary
thyroid carcinoma cell line differentiation. Cancer Res. 1995;55:2048-2052.
3.
Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and
disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.
JAMA. 1996;276(19):1575-1579.
4.
Eng C, Mulligan LM, Healey CS, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of
medullary thyroid carcinoma. Cancer Res. 1996b;56:2167-2170.
5.
Eng C, Mulligan LM, Smith DP, et al. Mutation in the RET proto-oncogene in sporadic medullary thyroid
carcinoma. Genes Chrom Cancer. 1995;12:209-212.
6.
Eng C, Smith DP, Mulligan LM, et al. Point mutation within the tyrosine kinase domain of the RET protooncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 1994;3:237241.
7.
Frilling A, Weber F, Tecklenborg C, Broelsch CE. Prophylactic thyroidectomy in multiple endocrine neoplasia:
The impact of molecular mechanisms of RET proto-oncogene. Langenbecks Arch Surg. 2003;388(1):17-26.
8.
Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: A review and update of genotype-phenotype
correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531544.
9.
Le HN, Norton JA. Perspective on RET proto-oncogene and thyroid cancer. Cancer J. 2000;6(2):50-57.
10. Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia
type 2: Report of the International RET Mutation Consortium. J Intern Med. 1995;238(4):343-346.