Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative...

Area of Science:

• Genetics and Molecular Biology
• Oncology
• Endocrinology

Background:

• Genetic analysis of the rearranged during transfection (RET) gene is crucial for identifying medullary thyroid cancer (MTC) risk.
• Novel sequence variants, such as RET I852M, present challenges in clinical interpretation, requiring further investigation to determine pathogenicity.

Observation:

• A three-generation Caucasian family with the RET I852M variant exhibited variable clinical presentations, including occult MTC and elevated calcitonin levels in some carriers.
• In vitro functional studies demonstrated that RET I852M mutant cells possess transforming and migratory activities, comparable to known class A RET mutations (e.g., V804M).
• The I852M mutation showed weaker proliferative and migratory potential compared to more aggressive RET mutations (class C C634R and class D A883F).

Findings:

• The RET I852M sequence variation is confirmed as a pathogenic mutation.
• This mutation is classified as a weakly activating RET germline mutation, falling under American Thyroid Association (ATA) class A.

Implications:

• The classification of RET I852M as a genuine mutation necessitates its inclusion in genetic screening protocols for MTC.
• Understanding the specific activity of RET I852M aids in risk stratification and personalized management strategies for individuals and families affected by MTC.
• This study clarifies the clinical significance of a previously unknown RET variant, improving diagnostic accuracy for hereditary thyroid cancer.