ACMG Criteria Reference Library
Population Data: PM2, BA1, BS1, BS2, PS4
Last Updated: October 11, 2025Introduction Accurate classification of genetic variants is fundamental to genomic medicine, directly influencing both clinical and research outcomes.The original ACMG/AMP (2015) guidelines introduced fixed population frequency thresholds for several criteria; however, these static cutoffs do not account for gene-specific or population-specific variability. To overcome these limitations, SeqSMART employs a data-driven, adaptive modeling approach that dynamically...
Computational Predictive Data: PP3, BP4, BP7
Last Updated: October 20, 2025Overview Computational predictive tools are essential for variant interpretation, providing quantitative evidence on how genetic changes may affect gene or protein function.Within the ACMG/AMP framework: While early ACMG guidelines did not specify which computational tools or thresholds to use, subsequent refinements by the ClinGen SVI Working Group introduced standardized approaches for meta-predictors and score-based evidence...
Functional Evidence: PS3 and BS3
Last Updated: October 11, 2025Overview Functional evidence provides some of the most direct insights into a variant’s biological effect.Within the ACMG/AMP framework, PS3 and BS3 represent strong criteria based on the results of in vitro or in vivo functional studies. However, because such data are often limited to a small subset of variants, SeqSMART combines AI-assisted literature mining, automated...
Segregation Evidence: PP1 and BS4
Last Updated: October 11, 2025Overview Segregation analysis evaluates how a variant tracks with disease within families and remains one of the most direct ways to assess clinical relevance.In the ACMG/AMP framework, PP1 supports pathogenicity when a variant co-segregates with the disease, while BS4 supports benignity when it fails to segregate as expected. Although segregation data are rarely available from...
Cis/Trans Configuration: PM3 and BP2
Last Updated: October 11, 2025Overview Zygosity and variant configuration play a crucial role in variant interpretation for autosomal recessive disorders.Two ACMG/AMP criteria — PM3 and BP2 — evaluate whether a variant occurs in trans (on opposite chromosomes) or in cis (on the same chromosome) with another pathogenic variant. SeqSMART integrates literature-derived evidence, AI-driven text mining, and case-based phasing analysis...
De Novo and Inheritance Pattern: PS2 and PM6
Last Updated: October 11, 2025Overview The PS2 and PM6 criteria from the ACMG/AMP (2015) guidelines assess de novo variant occurrence, providing crucial evidence for pathogenicity when a variant arises spontaneously rather than being inherited.These criteria are particularly important for dominant disorders where new mutations are a common cause of disease. SeqSMART implements both criteria using its integrated family analysis...
PM1 – Variant Located in a Mutational Hotspot or Critical Functional Domain
Last Updated: October 11, 2025Overview The PM1 criterion provides moderate-strength pathogenic evidence in the ACMG/AMP framework.It applies when a variant is located within a mutational hotspot or a critical and well-established functional domain of a gene — regions that are essential for protein activity and typically devoid of benign variation. ACMG Definition: “Located in a mutational hot spot and/or...
PS1 and PM5 – Same or Similar Amino Acid Changes at the Same Codon
Last Updated: October 11, 2025Overview The PS1 and PM5 criteria assess missense variants based on known pathogenic changes affecting the same codon in a gene.Both criteria leverage prior knowledge from ClinVar and other curated variant databases to infer the potential significance of new missense substitutions. These rules are particularly powerful because they connect novel observations to well-established pathogenic mechanisms...
PP2 and BP1 – Evaluating Gene-Specific Variant Tolerance
Last Updated: October 11, 2025Overview The PP2 and BP1 criteria assess whether missense variants are a common or unlikely disease mechanism for a specific gene.By analyzing gene-level tolerance to missense variation and the known mechanism of pathogenicity, these criteria provide valuable context for interpreting missense variants within disease-associated genes. 1. What Are PP2 and BP1? Criterion Definition Evidence Direction...
PM4 and BP3 – In-Frame Indels and Repeat Regions in Variant Interpretation
Last Updated: October 11, 2025Overview The PM4 and BP3 criteria evaluate in-frame insertions or deletions (indels) that alter protein length without disrupting the reading frame.These variants can either impact critical functional domains (PM4) or occur in repetitive, functionally neutral regions (BP3).By distinguishing between these contexts, SeqSMART ensures precise classification of variants that change protein structure but not its translation...
PVS1 – Interpreting Loss-of-Function (LoF) Variants in SeqSMART
Last Updated: October 11, 2025Overview Loss-of-function (LoF) variants — such as nonsense, frameshift, canonical splice site, initiation codon, or multi-exon deletions — can lead to loss or severe reduction of gene product activity. The ACMG/AMP 2015 guidelines designate PVS1 (“Pathogenic Very Strong”) for such variants in genes where LoF is an established disease mechanism.However, LoF interpretation requires context: not...
Previous Evidence: PP5, BP6, and BP5
Last Updated: October 11, 2025Overview 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...
PP4 – Phenotype Specificity Supporting Variant Pathogenicity
Last Updated: October 11, 2025Overview The PP4 criterion provides supporting-level evidence of pathogenicity in the ACMG/AMP framework.It applies when a patient’s phenotype or family history is highly specific for a genetic disorder known to have a single or limited genetic etiology.When applied correctly, PP4 adds strong contextual evidence that links a variant’s molecular finding to the observed clinical presentation....