This test analyzes the RET gene for pathogenic variants associated with the three subtypes of multiple endocrine neoplasia type 2 (MEN2): MEN2A, MEN2B and familial medullary thyroid cancer (FMTC). All three subtypes heighten the risk for medullary thyroid carcinoma (MTC) and other tumors.
The clinical presentation of MEN2 varies widely among affected individuals and their family members. Genetic testing may clarify the subtype and help identify those who are at high risk for MEN2-related tumors. Affected individuals may benefit from early and targeted screening of the conditions most commonly associated with MEN2, including medullary thyroid cancer, a condition that is preventable and that has an excellent prognosis when diagnosed at an early stage. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
MEN2A accounts for approximately 70%-80% of MEN2 cases and is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. MEN2B, which accounts for approximately 5% of MEN2 cases, is also characterized by medullary thyroid cancer (MTC) and pheochromocytoma, but not by parathyroid hyperplasia. Other clinical features may be present as well, including mucosal neuromas of the lips and tongue, distinctive facial features, intestinal ganglioneuromas, and a ‘marfanoid’ body habitus.
FMTC is characterized by medullary thyroid cancer (MTC) without the other clinical manifestations of MEN2A or MEN2B. More recently, FMTC has been reported as a variant of MEN2A with decreased penetrance of pheochromocytoma and hyperparathyroidism rather than a distinct subtype. FMTC accounts for approximately 10%-20% of MEN2 cases.
Lifetime cancer risks in individuals with pathogenic RET mutations are very high, particularly for medullary thyroid cancer.
|MEN2 subtype||Medullary thyroid cancer||Pheochromocytoma||Parathyroid hyperplasia||Other features|
|MEN2A||~100%||50% with <5% risk of malignant transformation||20%-30%||-|
|MEN2B||~100%||50% with <5% risk of malignant transformation||-||Mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, intestinal ganglioneuromas, ‘marfanoid’ body habitus|
Molecular genetic testing of RET identifies pathogenic variants in 98% of individuals with MEN2A and MEN2B and in approximately 95% of families with FMTC.
MEN2 is inherited in an autosomal dominant pattern. Approximately 5% of MEN2A cases occur as the result of a spontaneous de novo mutation and 50% of MEN2B cases are de novo.
The prevalence of MEN2 is approximately 1 in 35,000 individuals.
RET genetic testing may be considered for all individuals with at least one of the following:
Please see the following references for further details regarding clinical features suggestive of MEN2-related conditions:
For management recommendations, please refer to:
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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
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|