- Design
- Retrospective laboratory database analysis
- Population
- 2.6 million variants from 5.5 million individuals; 32,241 tracked from v4.2
- Primary outcome
- VUS reclassification and its relation to Sherloc score
- Effect
- 3,834 VUS reclassified, 73% via post-v4.2 criteria; score vs up/down ratio r² 0.95
This Journal of Molecular Diagnostics report, published 22 September, evaluated ten years of Sherloc, a points-based refinement of the 2015 ACMG/AMP variant classification guidelines, applied to 2.6 million variants from 5.5 million people referred for genetic testing.
Of 32,241 variants first classified under version 4.2, 3,834 variants of uncertain significance were later reclassified; 73% of those reclassifications relied on evidence criteria introduced after that version. Removing AI-related criteria from 615,341 recent classifications changed the result for 21.0%. The Sherloc score correlated strongly with the ratio of upgrades to downgrades (adjusted r² 0.95). High-scoring VUS were disproportionately resolved by cascade family testing or RNA analysis.
For laboratories and clinicians, the lesson is that a VUS is a moving target. Frameworks that update their evidence rules resolve more of them, and the score itself signals which way a VUS is likely to move.
- Treat a VUS as provisional and plan periodic reinterpretation.
- A higher points score suggests a VUS is more likely to be upgraded than downgraded.
- Offer cascade family testing or RNA analysis for high-scoring VUS where available.
- Record the classification framework and version on every variant report.
Why it matters
Shows that a variant report is only as current as the framework version behind it.
Don't overread it
This is one commercial laboratory's framework evaluated by its developers.
The statistics, in plain English
An adjusted r² of 0.95 means the score explained almost all the variation in the direction of reclassification across score bands, but only about half (0.49) of how often reclassification happened.
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