Variant Classification

Accurate classification of somatic mutations is essential for meaningful interpretation and informed clinical decision-making in oncology. At Strand Life Sciences, we follow gold-standard guidelines set forth by AMP/ASCO/CAP to assess and categorize somatic variants identified through next-generation sequencing (NGS) in cancer samples, including both solid and liquid biopsies.

Variant Classification Framework

Variants identified in tumor suppressor genes and oncogenes are categorized based on experimentally established or predicted effects on protein structure or function. Each variant is then labeled according to the most reliable available information regarding its validated or potential functional impact.

Loss of Function (LOF)

Variants that lead to a loss of the protein function, as established in published literature or extrapolated from evidence of loss of critical functional domains.

Gain of Function (GOF)

Variants that lead to a gain of the protein function, as established in published literature

Workflow for Clinical Interpretation of Variants

Step 1

Variant Detection

Somatic variants in cancer genes are identified through high-throughput sequencing

Step 2

Evidence Gathering

Strandomics aggregates and analyzes data from:

Public databases (e.g., ClinVar, HPO, dbSNP)
Proprietary somatic knowledgebase on 500+ genes, 20,000 variants, 100+ FDA-approved drugs, and 4,844 pathway interactions with manually curated molecular variant summaries and clinical therapy recommendations
In silico prediction tools to estimate how a variant might affect gene function
Functional and clinical evidence
Curated literature evidence

Step 3

Variant Classification

Based on experimentally established or predicted effects on protein structure or function, each variant is labeled according to the most reliably available information regarding its validated or potential functional impact.

Step 4

Clinical Interpretation

For reportable variants, our reports include clinically significant variant information including:

Gene-disease associations
Standard of care recommendations
Off-label and In-trial therapy recommendations
Clinical impact (Prognostic and diagnostic associations)

Step 5

AMP Tier Categorization

The variants are classified into four different tiers based on recommendations of the Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP) based on the strength of clinical and functional evidence.

Step 6

Expert Review

A team of variant scientists reviews the evidence and assigns a final classification.

Accurate classification of genetic variants is essential to ensure meaningful interpretation and informed clinical decision-making in hereditary cancer diagnostics. At Strand Life Sciences, we follow the gold-standard guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) to assess and classify germline variants identified during testing.

Variant Classification Framework

The ACMG and AMP (Association for Molecular Pathology) jointly developed a five-tier classification system to categorize sequence variants based on the strength of clinical and functional evidence. This framework ensures consistency, transparency, and clinical relevance in variant interpretation.

Pathogenic (Class 5)

Pathogenic variants have strong, well-established evidence showing they cause disease. These may include loss-of-function changes or well-known recurrent mutations seen in affected individuals. Their presence has clear clinical implications for diagnosis, management, and family testing.

Likely Pathogenic (Class 4)

Likely Pathogenic variants show strong evidence of disease association, though not definitive. They may lack full functional proof but are rare and often align with clinical presentation. When combined with family history or phenotype, they can support risk-based clinical decisions.

Variant of Uncertain Significance (VUS, Class 3)

Variants of Uncertain Significance (VUS) are reported with full transparency. These are variants for which current evidence is either limited, conflicting, or inconclusive regarding their role in disease.

VUSD (Variant of Uncertain Significance with probable damaging effect):

A subcategory of VUS, used when a variant shows multiple lines of evidence suggestive of a deleterious impact (e.g., predicted loss of function, deleterious in silico scores, rare in population databases), but does not yet meet the threshold for classification as Likely Pathogenic under ACMG guidelines.

VUSDs are flagged for high-priority re-evaluation as new data emerges.
Clinicians may consider closer monitoring or family studies when consistent with patient history or phenotype, but clinical decisions should remain cautious

Likely Benign (Class 2)

Likely Benign variants have data supporting a lack of disease association, though not enough for absolute certainty. These may appear in population databases or show benign computational results. They are not expected to impact health or clinical care.

Benign (Class 1)

Benign variants are conclusively non-pathogenic. Often common in the general population, these changes have no effect on gene function or disease risk. They are excluded from reports unless requested for reference or research.

Workflow for Clinical Interpretation of Variants

Step 1

Variant Detection

Germline variants in cancer predisposition genes are identified through high-throughput sequencing

Step 2

Evidence Gathering

Strandomics aggregates and analyzes data from:

Public databases (e.g., ClinVar, gnomAD)
In silico prediction tools
Functional studies
Co-segregation analysis
Literature curation

Step 3

Variant Classification

Each variant is assessed using the ACMG evidence codes (e.g., PVS1, PM2, BS1), weighted according to strength, and mapped to one of the five classes.

Step 4

Clinical Interpretation

For pathogenic and likely pathogenic variants, our reports include:

Gene-disease association
Mode of inheritance
Clinical management considerations
Family testing recommendations

Step 5

Expert Review

A team of molecular geneticists and variant scientists jointly review the evidence and assign a final classification.

Re-evaluating Variant Classifications

As the scientific understanding of variants evolves, so too must their classification. We regularly monitor literature, public databases, and internal data to reassess previously reported variants.

Triggers for Reclassification:

Notification and Updates

If a variant previously reported as a VUS is reclassified to pathogenic or likely pathogenic, we encourage the provider to opt for annual reanalysis to stay updated for clinically relevant variant classifications.