Ten years of a points-based variant framework: most VUS reclassifications came from newer criteria

Design

Retrospective evaluation of variant classification framework versions

Population

32,241 tracked variants; 615,341 recent classifications in simulation

Primary outcome

Reclassification of variants of uncertain significance

Effect

3,834 VUS reclassified; 73% relied on post-v4.2 criteria

Sherloc is a points-based refinement of the 2015 ACMG/AMP variant classification guidelines used by one large commercial laboratory, applied to 2.6 million variants in 5.5 million people across 19 versions. This study assessed what a decade of updates did to classifications.

Of 32,241 variants first classified under the earliest version tracked, 3,834 variants of uncertain significance had been reclassified by the end; 73% of these relied on evidence criteria added later. In a simulation on 615,341 recent classifications, removing criteria related to computational prediction changed 21% of them. The points score correlated strongly with the ratio of upgrades to downgrades.

High-scoring variants of uncertain significance were disproportionately resolved by cascade family testing or RNA analysis, though most variants resolved that way had low scores.

The practical lesson for laboratories and clinicians is that a VUS is a provisional label. Periodic re-review, and family or RNA studies where feasible, resolve a meaningful share.

• Treat a variant of uncertain significance as provisional and plan for re-review.
• Consider cascade family testing or RNA studies to help resolve a VUS.
• Do not act clinically on a VUS; wait for reclassification.
• Note that computational evidence now drives a substantial share of classifications.

Why it matters

Patients carrying a VUS often hear nothing more, yet 3,834 of the uncertain variants tracked here were eventually resolved.

Don't overread it

This describes one laboratory's framework; rates may differ elsewhere.

The statistics, in plain English

The adjusted r² of 0.95 means the score almost perfectly tracked whether reclassifications went up or down, but only 0.49 for whether a variant was reclassified at all, so the score predicts direction better than likelihood.

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