FeedbackMassively Parallel Sequencing
Related Tests
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification
Use to confirm a diagnosis of a hereditary cancer syndrome with personal or family history consistent with features of more than one cancer syndrome
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Multiple endocrine neoplasia type 2 (MEN2) is a hereditary syndrome caused by pathogenic variants in the RET gene. MEN2 is classified into subtypes MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). All MEN2 subtypes have an increased risk of medullary thyroid cancer (MTC). Additionally, MEN2A is associated with benign parathyroid adenomas/hyperplasia and pheochromocytoma (PCC). MEN2B is associated with more aggressive MTC that can occur during childhood, PCC, neuromas, eye anomalies, and distinctive physical features. FMTC is considered a variant of MEN2A and is characterized as multiple cases of MTC in a family, typically without the presence of PCC or hyperparathryoidism.
Disease Overview
Epidemiology
- Approximately 1 in 35,000 individuals have MEN2
- Approximately 25-30% of all individuals with MTC have a germline RET pathogenic variant
Symptoms
Genetics
Gene
RET (NM_020975)
Inheritance
Autosomal dominant
De novo Pathogenic Variants
Test Description
Clinical Sensitivity
Analytical Sensitivity/Specificity
For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) | Analytical Specificity (NPA) (%) |
|---|---|---|
|
SNVs |
>99 (96.9-99.4) |
>99.9 |
|
Deletions 1-10 bpb |
93.8 (84.3-98.2) |
>99.9 |
|
Insertions 1-10 bpb |
94.8 (86.8-98.5) |
>99.9 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced. bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
One RET pathogenic variant detected |
Consistent with a diagnosis of MEN2; MEN2 subtype depends on clinical features and specific variant identified |
|
Negative |
No RET pathogenic variants detected |
Diagnosis of MEN2A, MEN2B, or FMTC is unlikely but not excluded |
|
Inconclusive |
RET variant of unknown clinical significance detected |
Uncertain; it is unknown whether variant is benign or pathogenic |
Limitations
- A negative result does not exclude a diagnosis of MEN2.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the RET gene
- Regulatory region and deep intronic variants
- Large deletions/duplications in the RET gene
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Noncoding transcripts
- Low-level somatic variants
- Certain other variants due to technical limitations in the presence of pseudogenes or repetitive/homologous regions
References
-
Pathology and Genetics: Tumours of the Endocrine Organs.
DeLellis RA, Lloyd RV, Heitz PU. Pathology and genetics: tumours of the endocrine organs. World Health Organization Classification of Tumours Series. Vol 8. International Agency for Research on Cancer; 2004.
-
GeneReviews - Multiple Endocrine Neoplasia Type 2
Eng C. Multiple endocrine neoplasia type 2. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Aug 2019; Accessed: Nov 2021]
-
25810047
Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610.
-
22584709
Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):69-75.
-
8981969
Schuffenecker I, Ginet N, Goldgar D, et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Am J Hum Genet. 1997;60(1):233-237.
-
7977365
Carlson KM, Bracamontes J, Jackson CE, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55(6):1076-1082.
-
19469690
Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612.
-
7595170
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.
-
21552134
Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011;13(9):755-764.
33812987
Mathiesen JS, Effraimidis G, Rossing M, et al. Multiple endocrine neoplasia type 2: A reveiw. Semin Cancer Biol. 2021:S1044-579X(21)00085-7.
NCCN - thyroid carcinoma v 3.2021
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Thyroid carcinoma. Version 3.2021. [Updated: Oct 2021; Accessed: Nov 2021]
Use for diagnostic or predictive testing for multiple endocrine neoplasia type 2 (MEN2) syndrome, caused by pathogenic variants in the RET gene