Clinical Genomics & Precision Oncology
From raw sequencing files to accredited clinical diagnostic reports. Master CLIA/CAP analytical validation, the ACMG/AMP 5-tier variant classification criteria, molecular tumor board curation with OncoKB, TMB/MSI immunotherapy biomarkers, ctDNA liquid biopsies, and CPIC pharmacogenomics.
Curriculum Modules
Click on any chapter below to explore complete code, diagnostic guidelines, and clinical reporting algorithms.
1: Clinical NGS Standards: CLIA/CAP Regulations & Analytical Validation
CLIA/CAP regulatory accreditation, diagnostic sensitivity and specificity, Limit of Detection (LoD), Genome in a Bottle (GIAB) reference standards, and analytical validation protocols.
2: Inherited Disease Genomics: Trio Exomes & Mendelian Inheritance
Autosomal dominant, recessive, and X-linked inheritance, de novo mutation discovery, parent-offspring trio exome sequencing, and candidate gene prioritization.
3: The ACMG/AMP 5-Tier Variant Classification Framework
Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign, 28 evidence criteria (PVS1 null variants, PS1-4, PM1-6, PP1-5, BA1, BS1-4, BP1-7), and Bayesian point systems.
4: Databases for Clinical Variant Interpretation: ClinVar, ClinGen & HPO
ClinVar review stars, ClinGen Expert Panels, gnomAD allele frequency thresholds for disease prevalence, and Human Phenotype Ontology (HPO) clinical match scoring.
5: Precision Oncology: Driver Mutations, Oncogenes & Tumor Suppressors
Knudson's two-hit hypothesis, activating hotspot mutations (BRAF V600E, EGFR L858R), loss-of-function tumor suppressors (TP53, PTEN), and AMP/ASCO/CAP somatic tiers.
6: Molecular Tumor Boards & Actionable Biomarker Databases
OncoKB evidence levels, CIViC open clinical interpretation, Cancer Genome Interpreter (CGI), and automated therapeutic biomarker matching.
7: Tumor Mutational Burden (TMB) & Microsatellite Instability (MSI)
Calculating TMB (mut/Mb), TMB-High cutoffs (>=10 mut/Mb) for immune checkpoint inhibitors, mismatch repair deficiency (dMMR), and MSI-H algorithms (MSIsensor-pro).
8: Liquid Biopsy: Circulating Tumor DNA (ctDNA) & Minimal Residual Disease
Cell-free DNA (cfDNA) fragmentation physics (167 bp nucleosome footprint), duplex UMIs, calling ultra-low allele frequencies (VAF < 0.1%), and monitoring MRD.
9: Pharmacogenomics (PGx): CPIC Guidelines & Drug-Gene Pairs
Cytochrome P450 enzymes (CYP2D6, CYP2C19), star allele nomenclature, CPIC and PharmGKB clinical dosing guidelines (Warfarin, Clopidogrel, TPMT 6-mercaptopurine).
10: Whole-Genome Clinical Diagnostics: Deep Intronic & Regulatory Variants
SpliceAI for cryptic splice site prediction, non-coding promoter mutations (TERT -124 C>T), enhancer disruptions, and clinical Whole-Genome Sequencing (cWGS).
11: Repeat Expansion Disorders & Mitochondrial Genome Pathogenicity
Short tandem repeat expansions (Huntington CAG, Fragile X CGG, ALS C9orf72), ExpansionHunter CLI, mitochondrial heteroplasmy thresholds, and m.3243A>G MELAS.
12: Ethical, Legal, Social Implications (ELSI) & Genetic Counseling
Secondary and incidental findings (ACMG SF v3.2 list of 81 actionable genes), patient consent, right not to know, GINA non-discrimination act, and HIPAA/GDPR clinical compliance.
13: Building an Automated Clinical NGS Variant Reporting Pipeline
End-to-end clinical workflow: VCF input -> ClinGen/gnomAD/VEP annotation -> ACMG auto-classification (InterVar / AutoPVS1) -> PDF clinical diagnostic report generation.