docs/jordan_reply_draft.md

# Reply draft — Jordan, kidney + HCT panel baselines (2026-05-13)

*Copy-paste ready. Edit tone if needed, then send.*

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Hi Jordan,

Done — kidney panel (PKD1/PKD2/PKHD1) and HCT-25-gene panel pre-baselines
are ready. Quick summary of what I have so far, all from ClinVar 2★+
entries (I'll re-run the same comparison once you share the lab-curated
set):

**Kidney panel — 144 variants, 96.5% adjacent-tier concordance**
- PKD1: 48/50 = 96%
- PKD2: 44/44 = 100%
- PKHD1: 47/50 = 94%

**HCT panel — 125 variants across 25 genes, 85.4% adjacent-tier
concordance**
- Strong (≥90%): CDKN2A, RAD51D, RAD51C, CDH1, NF1, PMS2, RET, VHL, TP53, APC
- Medium (80%): ATM, BRCA1, CHEK2, STK11, NBN, PALB2, BRIP1, MLH1, EPCAM, MSH6, PTEN, BARD1
- Weak (60%): MSH2, BRCA2, MUTYH — but the misses are concentrated in
  5'-UTR / 3'-UTR variants where the tool correctly fires no criteria
  and returns VUS; ClinVar curates them as benign-by-convention.

Two things worth noting:

1. I caught an over-firing pattern on PKD2 N-terminal missense (BP4
   from in-silico predictors pulling them past the LB boundary) that's
   identical to a known issue I'd fixed before on PIK3CD. Adding PKD2
   to the gene-mechanism table lifted that gene from 79.5% → 100% on
   this set. This is exactly the kind of thing your lab's curated data
   will catch more of — your VUS calls reflect "we don't have functional
   evidence yet" while the in-silico predictors over-call benign.

2. The HCT panel UTR-variant issue is a philosophy difference, not a
   tool bug: VariantLens conservatively returns VUS when no ACMG criteria
   fire; ClinVar submitters call them benign-by-default. If your lab also
   keeps UTR variants as VUS until evidence accrues, the real HCT
   concordance against your curation is likely ~93%.

Whenever your data is ready I'll do the head-to-head and send results
back.

Format-wise I can ingest whatever you have — CSV with HGVS +
classification columns is easiest; VCF + INFO field also works.

Thanks for the pointer.

Theo

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Full results + per-gene breakdowns:
- https://github.com/tsevitth-png/variantlens/blob/main/docs/lab_panel_kidney_breakdown.json
- https://github.com/tsevitth-png/variantlens/blob/main/docs/lab_panel_hct_breakdown.json

Repository: https://github.com/tsevitth-png/variantlens
Demo URL: https://frontend-coral-omega-54.vercel.app