Multiple Endocrine Neoplasia Type 2, RET Sequencing

Use for diagnostic or predictive testing for multiple endocrine neoplasia type 2 (MEN2) syndrome, caused by pathogenic variants in the RET gene

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Use to confirm a diagnosis of a hereditary cancer syndrome with personal or family history consistent with features of more than one cancer syndrome

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

Clinical Characteristics by MEN2 Subtype
Subtype Proportion of MEN2 Cases Presence of MTC Presence of PCC Presence of Parathyroid Disease

MEN2A

70-80%

95%

50%

20-30%

MEN2Ba

~5%

100%

50%

Uncommon

FMTCb

10-20%

100%

0%

0%

aAdditional findings for the MEN2B subtype may include mucosal neuromas, gastrointestinal ganglioneuromatosis, medullated corneal nerve fibers, distinctive facies with enlarged lips, or marfanoid habitus.

bThe FMTC subtype may be part of an MEN2A disease spectrum, with decreased penetrance of PCC and hyperparathryoidism. 

Sources: Eng, 2019 ; Raue, 2012 

Genetics

Gene

RET (NM_020975)

Inheritance

Autosomal dominant

De novo Pathogenic Variants

  • 5% of MEN2A 
  • 50% of MEN2B 

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

Additional Resources