An integrated approach to reclassify MEN1 variants of uncertain significance using clinical and computational evidence
Authors' conclusion
Integrated re-evaluation combining phenotype, segregation, structural modelling, and computational prediction reduces diagnostic uncertainty and supports broader implementation of structured VUS reanalysis in MEN1.
Study context
- Population
- Individuals with germline MEN1 variants of uncertain significance (VUS), three Australian tertiary referral centres
- Participants
- 10 individuals
- Outcome
- Variant reclassification (ACMG/AMP criteria) and supporting clinical, computational and structural evidence
Methodological detailsthree tertiary referral centres
- Three tertiary referral centres
Main finding
As reported in the abstract
Reclassification of MEN1 VUS as likely pathogenic
Reclassified as likely pathogenic
7 of 10
70%
Remained VUS due to insufficient evidence
3
Observational data: associations, not effects.
Further findings
Computational scores vs ClinVar variants
- Median REVEL score of cohort variants
- 0.913
- AlphaMissense score of cohort variants
- 0.999
- Scores comparable to ClinVar LP/P variants and significantly higher than LB/B variants
- P < 0.001
- Kruskal-Wallis test
Structural modelling
- Clustering within constrained JunD- and MLL-binding domains of menin
Original publication
An integrated approach to reclassify MEN1 variants of uncertain significance using clinical and computational evidence. J Clin Endocrinol Metab. Published 25 June 2026. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →