genomics-variant-interpreter

name	genomics-variant-interpreter
description	Interpret genomic variants using ClinVar, gnomAD, and other genomic databases. Provides pathogenicity classification and clinical significance assessment.

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

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