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genomics-variant-interpreter

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Genomic Variant Interpretation

Interpret genomic variants by querying ClinVar, gnomAD, COSMIC, and other curated genomic databases. This skill provides ACMG/AMP-aligned pathogenicity classification, population frequency analysis, clinical significance assessment, and actionability evaluation for germline and somatic variants identified through clinical genomic testing.

Quick Install

npx skills add Open-Medica/open-medical-skills --skill genomics-variant-interpreter

What It Does

  • ACMG/AMP classification framework: Applies the American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology (AMP) five-tier classification system (Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign, Benign) with documented supporting criteria codes (PVS1, PS1-4, PM1-6, PP1-5, BA1, BS1-4, BP1-7)
  • Multi-database cross-referencing: Queries ClinVar for curated pathogenicity assertions and review status, gnomAD for population allele frequencies across diverse ancestries, COSMIC for somatic mutation frequency in cancer types, and OMIM for gene-disease associations
  • Population frequency analysis: Compares variant allele frequency across gnomAD populations (African, East Asian, European, Latino, South Asian) to identify ancestry-specific considerations and assess rarity using BA1 and BS1 frequency thresholds
  • Somatic variant annotation: For tumor-derived variants, provides COSMIC prevalence data, known driver/passenger classification, associated cancer types, and tier-level evidence for therapeutic relevance using the AMP/ASCO/CAP somatic variant classification system
  • Clinical actionability assessment: Links pathogenic/likely pathogenic variants to ClinGen-curated gene-disease validity classifications and actionability scores, identifying which findings warrant clinical intervention, surveillance, or cascade family testing

Clinical Use Cases

  • Germline genetic testing interpretation: A genetic counselor receives whole exome sequencing results for a patient with a family history of hereditary breast/ovarian cancer. The skill interprets a BRCA2 variant, pulling ClinVar consensus (pathogenic, 4-star review status), gnomAD frequency (<0.0001), and NCCN management recommendations
  • Tumor profiling analysis: An oncologist receives next-generation sequencing results from a solid tumor panel. The skill classifies each somatic variant by AMP/ASCO/CAP tier, identifies Tier I variants with FDA-approved companion diagnostics, and flags Tier II variants with clinical trial eligibility
  • Pharmacogenomic variant interpretation: A clinical pharmacologist needs to interpret CYP2D6 star allele combinations. The skill translates diplotype results into metabolizer phenotype predictions and links to CPIC dosing guidelines for affected medications
  • Variant reclassification monitoring: A molecular diagnostics lab re-evaluates a VUS reported two years ago. The skill checks for new ClinVar submissions, published functional studies, and updated population frequency data that may support reclassification

Safety & Evidence

  • Safety Classification: Restricted — Genomic variant interpretation directly influences clinical decision-making including surgical prophylaxis (e.g., risk-reducing mastectomy for BRCA carriers), targeted therapy selection, reproductive planning, and cascade family testing. All interpretations must be reviewed and signed out by a board-certified molecular pathologist or clinical geneticist. Variants of uncertain significance must never be used as the sole basis for clinical action. This skill provides interpretive support, not final clinical reports.
  • Evidence Level: High — Classification follows ACMG/AMP standards (Richards et al., 2015), somatic interpretation follows AMP/ASCO/CAP guidelines (Li et al., 2017), and all database annotations are sourced from expert-curated repositories (ClinVar, ClinGen, gnomAD). However, variant interpretation is an evolving field and classifications may change as new evidence emerges.

Example Usage

Germline variant interpretation:

Interpret variant: NM_000059.4(BRCA2):c.5946delT (p.Ser1982ArgfsTer22)
Clinical context: 38-year-old female with family history of breast cancer
(mother diagnosed at 42, maternal aunt at 45)

Variant Interpretation:

Variant: BRCA2 c.5946delT (p.Ser1982ArgfsTer22) Type: Frameshift deletion causing premature termination codon ACMG Classification: Pathogenic

Evidence supporting pathogenicity:

  • PVS1 (Very Strong): Null variant (frameshift) in BRCA2, a gene where loss of function is a known disease mechanism
  • PS1 (Strong): Same amino acid change previously established as pathogenic in ClinVar (87 submissions, 4-star review status, all concordant pathogenic)
  • PM2 (Moderate): Absent from gnomAD population databases (0/251,354 alleles)
  • PP1 (Supporting): Co-segregates with disease in multiple affected families in published literature

gnomAD frequency: Not observed (0.000000) ClinVar: Pathogenic (4-star consensus, 87 submitters) OMIM: Associated with Hereditary Breast-Ovarian Cancer Syndrome (OMIM #612555)

Clinical actionability:

  • Refer to cancer genetics for comprehensive risk assessment
  • NCCN recommends enhanced breast surveillance (annual MRI + mammography starting at age 25) and discussion of risk-reducing surgery
  • Cascade genetic testing recommended for at-risk first-degree relatives
  • Ovarian cancer risk management per NCCN guidelines

Technical Details

  • Category: Clinical Research Summarizing
  • Author: OMS Contributors
  • License: MIT
  • Version: 1.0.0
  • Specialty: Medical Genetics, Genomics

References

  • Richards S, et al. "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP." Genet Med. 2015;17(5):405-424.
  • Li MM, et al. "Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of AMP, ASCO, and CAP." J Mol Diagn. 2017;19(1):4-23.
  • ClinVar database (NCBI) — ncbi.nlm.nih.gov/clinvar/
  • gnomAD (Genome Aggregation Database) — gnomad.broadinstitute.org
  • ClinGen Clinical Genome Resource — clinicalgenome.org
  • COSMIC (Catalogue of Somatic Mutations in Cancer) — cancer.sanger.ac.uk/cosmic

This skill is part of Open Medical Skills, a curated marketplace of medical AI skills maintained by physicians for physicians and the healthcare industry.