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Previous Evidence: PP5, BP6, and BP5

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Overview #

The ACMG/AMP (2015) framework includes three criteria related to previously established evidence from reputable external sources: PP5, BP6, and BP5.
These criteria evaluate whether a variant’s classification has been consistently confirmed or contradicted by credible laboratories, databases, or case reports, and whether it has been observed in cases with unrelated molecular causes.

SeqSMART automates the evaluation of these criteria through dynamic ClinVar integration, AI-assisted literature mining, and temporal filtering to ensure that only current and authoritative evidence contributes to variant interpretation.

1. PP5 – Reputable Source Identifies Variant as Pathogenic #

ACMG Definition #

“Reputable source recently identifies a variant as pathogenic.”

SeqSMART Implementation #

SeqSMART automatically detects and applies PP5 when a recognized laboratory or database classifies a variant as Pathogenic or Likely Pathogenic (P/LP) under the ACMG/AMP framework.

ClinVar Integration #

  • SeqSMART continuously synchronizes with ClinVar to import variant classifications.
  • Only submissions made after 2015 (post-ACMG publication) are used to ensure guideline alignment.
  • If at least one authoritative source lists a variant as P/LP, PP5 is considered met (Supporting).

AI Literature Model #

SeqSMART’s AI-driven text-mining engine also searches:

  • Scientific publications,
  • Disease-specific variant databases, and
  • Laboratory curation repositories
     for recent classifications or re-evaluations confirming pathogenicity.

When such a classification is detected from a verified source, it strengthens the application of PP5.

Conflict Management #

When multiple ClinVar entries exist:

  • SeqSMART reviews the three most recent submissions only.
  • Older or withdrawn classifications are disregarded.
  • If recent classifications conflict, the system flags the variant for manual review rather than automatic PP5 assignment.

2. BP6 – Reputable Source Identifies Variant as Benign #

ACMG Definition #

“Reputable source recently identifies a variant as benign.”

SeqSMART Implementation #

BP6 applies when an authoritative laboratory or database has identified the variant as Benign or Likely Benign (B/LB).
This provides supporting benign evidence under the ACMG framework.

ClinVar Integration #

  • SeqSMART evaluates all post-2015 ClinVar records for Benign or Likely Benign classifications.
  • If an authoritative submission supports benignity and no conflicting evidence exists, BP6 is automatically applied.

AI Literature Model #

The AI model independently reviews:

  • Recent scientific articles and
  • Genetic case reports
     to identify new benign reclassifications or confirmations by clinical laboratories.

Conflict Management #

When conflicting interpretations exist:

  • SeqSMART again considers only the last three ClinVar submissions.
  • The system prioritizes the most recent, concordant evidence and flags conflicting cases for expert confirmation.

3. BP5 – Variant Found in Case with Alternate Molecular Basis for Disease #

ACMG Definition #

“Variant found in a case with an alternate molecular basis for disease.”

SeqSMART Implementation #

BP5 applies when a variant is detected in a patient whose disease phenotype can already be fully explained by another molecular event — suggesting that the observed variant is likely non-pathogenic.

ClinVar and Literature Integration #

SeqSMART reviews:

  • ClinVar entries describing individuals or families with alternative causative variants.
  • Scientific literature documenting cases in which a variant co-occurs with another known pathogenic variant that fully explains the disease phenotype.

If the presence of a second, causative mutation accounts for the phenotype, BP5 is applied as Supporting Benign evidence.

AI Evidence Discovery #

SeqSMART’s AI model continuously monitors:

  • PubMed publications,
  • Variant curation platforms, and
  • Case-level genomic repositories
     to identify reports where alternate molecular explanations exist.
    When confirmed, this evidence is incorporated to strengthen BP5 evaluation.

4. Data Integrity and Curation Framework #

SeqSMART enforces strict data governance to ensure that only valid and up-to-date information contributes to PP5, BP6, or BP5:

ProcessDescription
Temporal FilteringOnly ClinVar classifications submitted after 2015 are used to maintain ACMG/AMP compliance.
Conflict ResolutionThe system evaluates the three most recent ClinVar entries per variant and excludes outdated or contradictory records.
TransparencyAll ClinVar classifications are displayed in the SeqSMART interface for each variant, including submission date, laboratory name, and assertion strength.
User ControlExperts can manually override, confirm, or reject system-assigned PP5/BP6/BP5 designations, ensuring alignment with laboratory judgment.

5. Example Scenarios #

ScenarioObserved EvidenceCriterion Applied
ClinVar and recent literature list variant as pathogenic by multiple labsRecent, authoritative classifications support pathogenicity✅ PP5
ClinVar lists variant as benign with consistent supporting evidenceVariant consistently classified as benign across reputable submissions✅ BP6
Variant found in case where disease is caused by another known mutationPhenotype explained by alternative molecular cause✅ BP5
Conflicting ClinVar entries or outdated submissionsMixed or uncertain evidence⚠️ Flagged for expert review (no automatic assignment)

6. Transparency and Expert Flexibility #

  • SeqSMART displays all supporting and conflicting ClinVar entries, allowing full visibility of the decision process.
  • Experts can accept, modify, or disable PP5/BP6/BP5 assignments as needed.
  • Each change is logged with author, timestamp, and justification for auditable traceability.

Summary #

PP5, BP6, and BP5 integrate external variant knowledge from authoritative databases and literature to provide contextual support for classification.
SeqSMART ensures that these criteria are applied using post-2015, high-quality evidence, balancing automation with expert oversight for accuracy and transparency.

SeqSMART Evidence Integration Principle:
 Trust reliable sources — but verify recency and context.