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

ABSTRACT

Pheochromocytoma/paraganglioma (Pheo/PGL) associated with pituitary adenoma (PA) is rare in clinical practice, and a common pathogenic mechanism has been suggested owing to the germline pathogenic variants found in some cases. Our aim is to propose a reassignment for a recurrent MEN1 genetic variant found in a 54-year-old male patient with bilateral pheochromocytoma and GH-secreting PA. Pheo/PGL genes study was carried out in DNA samples from Pheo as well as PA and no pathological variants or large deletions were detected. Additionally, a MEN1 gene analysis was performed, and a heterozygous germline variant in exon 10 c.1618C>T; p.(Pro540Ser) was found. No MEN1 gene deletions/duplications were detected. In evaluating a causal relationship between the c.1618C>T MEN1 variant and both tumors, we took into account that missense variants are common pathogenic variants in MEN1, and the population frequency of this variant is too high to be considered pathogenic. His son (aged 38 and carrier) is asymptomatic, and computational analysis showed discrepancies. We propose that this recurrent variant, previously considered as likely pathogenic, subsequently as variant of uncertain significance, and likely benign should now be reclassified as benign.