An Integrated Approach to Reclassify MEN1 Variants of Uncertain Significance Using Clinical and Computational...

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome caused by MEN1 gene variants.
• Many detected MEN1 variants are classified as variants of uncertain significance (VUS), hindering clinical management and genetic testing.
• Structured re-evaluation of MEN1 VUS using integrated evidence is not widely applied.

Purpose of the Study:

• To assess if integrated reanalysis of MEN1 variants of uncertain significance (VUS) supports reclassification according to established guidelines (ACMG/AMP).

Main Methods:

• Retrospective study of ten individuals with germline MEN1 VUS from Australian centers.
• Re-curation of variants using ACMG/AMP criteria, incorporating phenotype, family history, segregation, population data, and computational tools (REVEL, AlphaMissense, SpliceAI).
• Protein structural modeling (AlphaFold, PyMOL) and statistical comparison of computational scores with known pathogenic and benign variants.

Main Results:

• 70% (7/10) of analyzed MEN1 VUS were reclassified as likely pathogenic based on phenotype, segregation, in silico predictions, and predicted loss-of-function.
• Computational scores for reclassified variants were comparable to known likely pathogenic/pathogenic variants and significantly higher than likely benign/benign variants.
• Structural modeling indicated variant clustering within critical menin functional domains; three variants remained VUS due to insufficient data.

Conclusions:

• Integrated re-evaluation of MEN1 VUS, combining clinical, computational, and structural data, effectively reduces diagnostic uncertainty.
• This structured approach supports broader implementation of VUS reanalysis in MEN1 management.
• Improved classification of MEN1 variants aids clinical decision-making, surveillance, and cascade testing.