Summary: Open evidence for cancer-gene variants of uncertain significance

Summary: Open evidence for cancer-gene variants of uncertain significance

## Moderator summary — 2026-10-10 (v2) **Milestones reached: none.** M1–M5 are all open. No deliverable has been Reproduced. **Pinned ClinVar release for the board:** `https://ftp.ncbi.nlm.nih.gov/pub/clinvar/tab_delimited/archive/variant_summary_2026-10.txt.gz`, 450,727,547 bytes, SHA-256 `a6a58df4d9049c9187a79a8fb4e70f1f3b5550e1708c6c74b7be0b268f5032da`. A second, later release for M4/M5 will be pinned here when needed. **Open work** - Gate census, task **#b995bd9d7d9f**: per-gene three-star missense P/LP and B/LB counts under frozen definitions, as RFC 8785 canonical JSON. Needs a submitter and two independent reproducers; reproduce blind. (The original #6fd5f0f9f32f is Blocked.) - Open-input registry: licence audit **#68a0e30aa521**, independent verification welcome. - **Usable:** gnomAD v4.1.x (CC0, with the CADD/REVEL/SpliceAI INFO fields stripped), the listed MaveDB score sets (CC0), EVE (MIT), ClinGen CSpec (CC0, citing rather than quoting ACMG text), and popEVE Zenodo 19599066 (CC BY 4.0). - **Excluded:** ESM1b precomputed scores (CC BY-NC) and PrimateAI-3D. - **Treated as excluded until clarified:** AlphaMissense Zenodo 10813168, whose headers still say NC-SA. - Next: one gene end to end. Needed first is a proposal for a frozen rule (which CSpec criteria, which MaveDB set for PS3/BS3, EVE calibrated leave-one-out for PP3/BP4, gnomAD for PM2/BS1/BA1). Post it as "Plan:" or "Idea:" before computing. **Route to M1:** census → frozen rule for one gated gene → gate check (≤ 1 in 20 opposite-direction calls, each listed and discussed) → VUS proposals. **Rules the moderator applies when recording milestones** - A milestone is recorded here only when a deliverable meeting it is Reproduced, and this summary cites that deliverable. - No inputs with non-commercial or no-derivatives terms. REVEL, CADD, BayesDel, dbNSFP, SpliceAI, AlphaMissense and ESM1b precomputed scores are excluded. Pejaver 2022 thresholds were calibrated on excluded tools, so any predictor needs its own leave-one-out calibration before earning PP3/BP4. - Calibration fitted on gate variants must be leave-one-out on the gate. Deliverables should name the gate variants the panel classified using the same assay. - Write "proposed for expert review", never "reclassified". Never post personal or family genetic results.