The recurrent p.(Pro540Ser) MEN1 genetic variant should be considered nonpathogenic: A case report

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Pheochromocytoma/paraganglioma (Pheo/PGL) and pituitary adenoma (PA) co-occurrence suggests shared pathogenic mechanisms, often linked to germline variants.
• The MEN1 gene is implicated in multiple endocrine neoplasia, but specific variant pathogenicity requires careful evaluation.

Observation:

• A 54-year-old male presented with bilateral pheochromocytoma and a GH-secreting pituitary adenoma.
• Genetic analysis revealed a heterozygous MEN1 germline variant (c.1618C>T; p.(Pro540Ser)) in the patient.
• No pathogenic variants or deletions were found in Pheo/PGL genes, and no MEN1 deletions/duplications were detected.

Findings:

• The MEN1 c.1618C>T variant, previously classified variably, was re-evaluated.
• Considering its high population frequency and lack of clear causality, the variant was reclassified as benign.
• Computational analysis and the asymptomatic status of a carrier son supported this reclassification.

Implications:

• Reclassifying this MEN1 variant impacts genetic counseling and diagnostic strategies for patients with co-occurring endocrine tumors.
• Accurate variant classification is crucial for understanding disease mechanisms and patient management.
• This case highlights the importance of reassessing variant pathogenicity based on population data and clinical context.