Germline pathogenic variant in ATM, CHEK2, or CDK12 (composite HRR-pathway RF). Disease-s...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-PAN-ATM-CHEK2-CDK12-PARPI-CANDIDATE`
Type	Red flag
Status	reviewed 2026-04-29 \| pending_clinical_signoff
Diseases	`DIS-BREAST` `DIS-PDAC` `DIS-PROSTATE`
Sources	`SRC-ESMO-PROSTATE-2024` `SRC-NCCN-BREAST-2025` `SRC-NCCN-PROSTATE-2025` `SRC-PROFOUND-DEBONO-2020`

Red Flag Origin

Definition	Germline pathogenic variant in ATM, CHEK2, or CDK12 (composite HRR-pathway RF). Disease-specific evidence varies sharply: ATM contributes to PROfound cohort-A (mCRPC) — pooled with BRCA1/2 for olaparib mPFS 7.4 vs 3.6 mo (HR 0.34). CDK12 — strong prostate-specific actionability (cohort-B in PROfound; immune-hot phenotype with elevated tumor neoantigens — emerging immunotherapy / PARPi rationale). CHEK2 — moderate-penetrance breast/prostate risk gene; weakest PARPi-response evidence (cohort-B in PROfound, smaller absolute benefit). Pan-tumor framing: treatment-modifying primarily in mCRPC; informational MDT signal in breast / pancreatic / ovarian where label-grade evidence is absent.
Clinical direction	intensify
Category	high-risk-biology

Trigger Logic

{
  "any_of": [
    {
      "finding": "atm_germline",
      "value": "pathogenic"
    },
    {
      "finding": "chek2_germline",
      "value": "pathogenic"
    },
    {
      "finding": "cdk12_germline",
      "value": "pathogenic"
    },
    {
      "finding": "atm_status",
      "value": "pathogenic"
    },
    {
      "finding": "chek2_status",
      "value": "pathogenic"
    },
    {
      "finding": "cdk12_status",
      "value": "pathogenic"
    },
    {
      "finding": "hrr_panel_atm_chek2_cdk12",
      "value": "positive"
    }
  ],
  "type": "biomarker"
}

Notes

Composite RF references BIO-ATM-CHEK2-CDK12-GERMLINE. Distinct from RF-PROSTATE-HIGH-RISK-BIOLOGY (which keys on broad hrr_pathway_mutation flag) — this RF surfaces gene-specific findings for nuanced MDT discussion. Algorithm wiring restricted to ALGO-PROSTATE-MCRPC-1L because that is the only disease with label-grade PARPi evidence; breast / pancreatic listed under relevant_diseases for MDT awareness without algorithm shift. CDK12 + immunotherapy is an active research signal — flag for clinical trial referral consideration. CHEK2 c.1100delC contributes ~moderate breast risk; counseling differs from BRCA1/2.

Used By

Indications

IND-PROSTATE-MCRPC-2L-CABAZITAXEL - IND-PROSTATE-MCRPC-2L-CABAZITAXEL
IND-PROSTATE-MCRPC-2L-DOCETAXEL - IND-PROSTATE-MCRPC-2L-DOCETAXEL