ResistanceMutationReportabilityChecker

URS & FS — User Requirements and Functional Specification

This document describes the controlled interface and behaviour of ResistanceMutationReportabilityChecker for Resistance Mutation Reportability Checker.

Domain limits and critical parameters

• Performs specialized verification of resistance variants per AMP/ASCO/CAP Tiering v2, NCCN Therapy Guidelines, ESMO Precision Medicine and FDA CDx labeling: technical reliability (above LOD, supporting reads ≥3, UMI confirmation for low-VAF, no strand bias/artifacts), resistance annotation (drug association, mechanism, type, evidence level, knowledge base source and rating), clinical context consistency (acquired resistance requires prior drug exposure, line of therapy), alternative therapy iden
• ⚠️ Critical: Resistance is ALWAYS context-dependent; variant may be resistant to one drug and sensitive to another. "Acquired" without prior exposure = annotation or history error. Uncertain KB rating ≠ automatically reportable; requires expert review. Cross-resistance to alternatives must be explicitly stated; omission = ineffective therapy prescription. Preclinical evidence without trials = incomplete report. Novel variants require curation time; do not release without expert approval. Standar

URS — User Requirements Specification

input.csv contract

SampleID,PatientID,PrimaryTumorType,DetectedVariant,Gene,VariantType,AssociatedDrug,ResistanceMechanism,ResistanceType,EvidenceLevel,KnowledgeBase_Source,VariantInKnowledgeBase,KnowledgeBase_ResistanceRating,CurrentTherapy,PriorTherapies,PatientCurrentlyOnAssociatedDrug,PatientPreviouslyOnAssociatedDrug,LineOfTherapy,AlternativeTherapy_Available,AlternativeTherapy_Names,CrossResistance_ToAlternatives,CrossResistantDrugs,VAF_Percent,AssayLOD_Percent,AboveLOD,SupportingReads,MinSupportingReads,UMI_Confirmed,StrandBias_Detected,ArtifactFlag_Raised,ProposedTier,TierAssignment_Valid,InterpretationText_Complete,DrugName_Standardized,MechanismDescribed_InReport,ClinicalTrialOptions_Listed,NovelResistanceVariant,ConflictingEvidence,ComplexResistance_Pattern,RequiresMDT_Discussion
RES-2026-001,PAT-LUNG-042,NSCLC,EGFR:c.2369C>T (p.T790M),EGFR,SNV,Osimertinib,On_Target_Gatekeeper,Acquired,FDA_Label,OncoKB,true,Resistant,Osimertinib,Erlotinib;Chemotherapy,true,true,Second_Line,true,Amivantamab+Lazertinib;Chemotherapy;Clinical_Trial,false,,12.5,0.1,true,850,3,true,false,false,Tier_I_Level_A,true,true,true,true,true,false,false,false,false
RES-2026-002,PAT-CRC-055,CRC,KRAS:c.183A>T (p.Q61H),KRAS,SNV,Cetuximab,Off_Target_Bypass,Primary,Preclinical,CIViC,true,Uncertain,FOLFOX+Cetuximab,,true,false,First_Line,true,Bevacizumab+FOLFIRI,false,,8.2,0.1,true,420,3,true,false,false,Tier_II_Level_D,false,false,true,false,false,false,true,false,true
RES-2026-003,PAT-BRCA-061,Breast,ESR1:c.1619G>A (p.Y537S),ESR1,SNV,Tamoxifen,On_Target_Activating,Acquired,Guideline,OncoKB,true,Resistant,Letrozole,Tamoxifen,false,true,Third_Plus,true,Fulvestrant;Elacestrant,false,,0.05,0.1,false,2,3,false,true,true,Tier_I_Level_A,true,true,true,true,true,false,false,false,false

Input validation rules

FS — Functional Specification

Example output.json

{
  "utilityId": "resistancemutationreportabilitychecker",
  "utilityFolder": "ResistanceMutationReportabilityChecker",
  "package": "LiquidBiopsy",
  "overallStatus": "PASS|WARNING|FAIL",
  "sourceFile": "input.csv",
  "processedAtUtc": "2026-06-10T00:00:00Z",
  "checks": [
    {
      "parameter": "SampleID",
      "value": "RES-2026-001",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-001"
    },
    {
      "parameter": "PatientID",
      "value": "PAT-LUNG-042",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-002"
    },
    {
      "parameter": "PrimaryTumorType",
      "value": "NSCLC",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-003"
    },
    {
      "parameter": "DetectedVariant",
      "value": "EGFR:c.2369C>T (p.T790M)",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-004"
    },
    {
      "parameter": "Gene",
      "value": "EGFR",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-005"
    },
    {
      "parameter": "VariantType",
      "value": "SNV",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-006"
    },
    {
      "parameter": "AssociatedDrug",
      "value": "Osimertinib",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-007"
    },
    {
      "parameter": "ResistanceMechanism",
      "value": "On_Target_Gatekeeper",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-008"
    },
    {
      "parameter": "ResistanceType",
      "value": "Acquired",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-009"
    },
    {
      "parameter": "EvidenceLevel",
      "value": "FDA_Label",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-010"
    },
    {
      "parameter": "KnowledgeBase_Source",
      "value": "OncoKB",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-011"
    },
    {
      "parameter": "VariantInKnowledgeBase",
      "value": "true",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-012"
    }
  ],
  "criticalFindings": [],
  "warnings": [],
  "audit": {
    "inputHash": "sha256:<calculated at runtime>",
    "rulesVersion": "<utility executable version>",
    "documentation": "ResistanceMutationReportabilityChecker.documentation.html"
  }
}

Traceability matrix

IQ/OQ/PQ test scenarios

QA/QC and change control

• Do not rename columns without updating validator, documentation and test set.
• Retain input.csv, output.json, executable version and checksum.
• Before production use, perform IQ/OQ/PQ or equivalent CSV/CSA verification.
• Critical limits shall be verified against the approved specification, registration dossier and local SOPs.
• The utility provides structured QC decision support; final release decision remains with QA/QP and approved procedures.