Introduction #
SeqSMART fully implements the ACMG/AMP variant classification guidelines, which remain the international standard for assessing variant pathogenicity.
However, the genomic interpretation field has evolved significantly since the original ACMG/AMP framework was introduced in 2015. Expert panels — particularly the ClinGen Expert Panels — have refined and reinterpreted several criteria to increase accuracy and disease specificity.
SeqSMART follows these ClinGen-aligned modifications to ensure its classifications reflect the most up-to-date clinical and scientific standards.
At the same time, the platform acknowledges that expert judgment remains the ultimate authority when evidence interpretation diverges from predefined rules.
1. The Evolving Nature of ACMG/AMP #
Over the last decade, numerous expert groups have contributed to refining the ACMG/AMP framework:
- ClinGen (Clinical Genome Resource) has issued condition- or gene-specific recommendations, adjusting rule strengths, combining criteria, and clarifying edge cases.
- Disease-specific working groups have published modified scoring systems for certain gene classes (e.g., mitochondrial disorders, cancer predisposition genes).
- Clinical laboratories and consortia have added internal calibration rules based on empirical data and collective experience.
SeqSMART continuously incorporates these revisions, updating its ACMG logic engine and evidence evaluation methods in line with ClinGen-approved refinements.
2. Respecting Expert Opinion #
The ACMG/AMP guidelines explicitly recognize that expert judgment can override strict algorithmic interpretation when justified by evidence.
SeqSMART fully supports this principle, enabling authorized reviewers to:
- Override the system’s automated classification when expert consensus suggests a different interpretation.
- Adjust the strength of individual rules (e.g., downgrading PM2 or upgrading PS4) based on case-specific evidence.
- Document the rationale behind every modification for transparency and auditability.
All expert actions are recorded in the case audit log, preserving the traceability of decisions and their underlying reasoning.
3. The Expert Discussion Space #
SeqSMART introduces a dedicated Expert Discussion Space — a collaborative environment designed for professionals to debate, justify, and consolidate variant interpretations.
Key Features: #
- Experts can initiate or join structured discussions for specific variants or cases.
- Discussion threads support attaching evidence, references, or computational results.
- Voting or agreement functions allow experts to collectively validate interpretations.
- Each discussion remains linked to the variant record, ensuring persistent context.
This feature bridges the gap between automated logic and the professional discourse that drives precision medicine.
4. Integrating Expert Consensus Using LLM Assistance #
To enhance collaboration efficiency, SeqSMART leverages its integrated Large Language Model (LLM) to process expert discussions intelligently.
When discussions reach a consensus:
- SeqSMART’s LLM automatically summarizes the conversation, capturing the key arguments, literature references, and final conclusion.
- The summary is submitted to the discussion participants for review and acceptance.
- Upon acceptance, the consensus note is published for that specific variant.
- After internal curation and verification, the validated expert opinion becomes visible to all users alongside the official SeqSMART classification.
This process creates a living layer of expert knowledge, continuously enriching the variant database beyond static rule-based logic.
5. Customization Options for Expert Reviewers #
SeqSMART offers several mechanisms for experts to customize or refine ACMG evaluations:
| Customization Level | Description |
| Rule Adjustment | Modify individual criteria strengths or mark criteria as “Not Applicable.” |
| Classification Override | Replace system-generated classification with an expert-derived interpretation. |
| Annotation Additions | Add literature references, PubMed IDs, or institutional notes. |
| Expert Consensus Integration | Accept and apply published discussion outcomes to institutional workflows. |
| ClinGen Alignment Updates | Automatically adopt newly approved ClinGen refinements once released. |
Each change is version-controlled and timestamped for reproducibility and data integrity.
6. Transparency and Curation #
Expert overrides and discussion-based conclusions are handled with full transparency and quality assurance:
- All modifications include author identity, timestamp, and justification.
- Curation team review ensures that expert conclusions are evidence-based and consistent with current ClinGen or ACMG interpretations.
- Published expert opinions are clearly labeled as community-derived insights and are displayed beside the SeqSMART classification on the variant page.
This ensures clarity between automated system output and validated expert interpretation.
7. The Power of Collaborative Expertise #
SeqSMART’s approach represents a next-generation interpretation model — one that values data-driven automation while enabling human expertise to refine, challenge, and improve the system.
By combining formal ACMG/AMP logic, ClinGen compliance, and collaborative expert discussions, SeqSMART builds a continuously evolving knowledge ecosystem where every classification reflects both evidence and expertise.
SeqSMART empowers experts to go beyond static ACMG classification by integrating consensus, conversation, and human insight into the interpretation process.
Through ClinGen alignment, role-based override permissions, and AI-assisted discussion summaries, SeqSMART ensures that every variant classification is both scientifically grounded and professionally validated.SeqSMART Expert Collaboration Principle:
When evidence meets experience, knowledge evolves.