What are the limitations of the acmg amp variant classifier?

While the acmg amp variant classifier is highly validated, it should not replace clinical judgment. OpiCalc provides the latest evidence-based limitations for the acmg amp variant classifier to ensure safe bedside use and optimal diagnostic accuracy.

How does the acmg amp variant classifier compare to other MedicalGenetics scores?

The acmg amp variant classifier is a gold-standard diagnostic tool. OpiCalc provides side-by-side clinical guidance to help clinicians choose the most specific evidence-based tool for their patient's presentation.

Is the acmg amp variant classifier free to use?

Yes. OpiCalc provides the acmg amp variant classifier completely ad-free and optimized for mobile bedside use, ensuring you can calculate medical risk swiftly and without distraction.

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ACMG/AMP Variant Classifier Amsterdam Criteria II CYP2C19 Phenotype Interpreter DLCN Score (FH)GJB2 Variant Interpreter Ghent-2 Criteria (Marfan)HTT CAG Repeat (Huntington)Hereditary Thrombophilia VTE Risk Revised Bethesda Guidelines Schwartz Score (LQTS)Tyrer-Cuzick Breast Risk

ACMG/AMP Variant Classifier

ACMG/AMP Variant Classification (2015)

Select all applicable evidence criteria. The framework combines evidence strength to generate a 5-tier variant classification (P → LP → VUS → LB → B). This is a decision-support tool — final classification requires expert molecular pathologist review.

Pathogenic Evidence Criteria

Benign Evidence Criteria

Guidelines & Evidence

Clinical Details

Section 1

When to Use

Interpreting variants identified in clinical genetic testing panels, exomes, or whole-genome sequencing.

Classifying germline variants from hereditary cancer, cardiovascular, neurological, or metabolic gene panels.

Structuring evidence for VUS (Variant of Uncertain Significance) review and reclassification decisions.

Standard framework used by all ACMG-accredited clinical laboratories and required for CAP/CLIA certification.

Section 2

Formula & Logic

5-Tier Classification

Class	Designation	Clinical Action
5	Pathogenic (P)	Report; act on clinically
4	Likely Pathogenic (LP)	Report; act on clinically (≥90% probability pathogenic)
3	Variant of Uncertain Significance (VUS)	Report; do NOT act on alone; family studies
2	Likely Benign (LB)	Do not report as actionable; may include as note
1	Benign (B)	Do not report

Evidence Criteria (Select)

Code	Criterion	Strength
PVS1	Null variant (LOF) in gene where LOF is a mechanism	Very Strong Pathogenic
PS1	Same amino acid change as established pathogenic variant	Strong Pathogenic
PS2	De novo (confirmed) in patient with disease, no family history	Strong Pathogenic
PS3	Functional assay shows damaging effect	Strong Pathogenic
PM2	Absent or low freq in gnomAD (< 0.1% for recessive, < 0.01% for dominant)	Moderate Pathogenic
PM5	Novel missense at position previously established as pathogenic	Moderate Pathogenic
PP3	Multiple computational tools predict pathogenic	Supporting Pathogenic
BS1	Allele frequency too high for disorder	Strong Benign
BA1	MAF > 5% in gnomAD	Stand-Alone Benign

Classification Rules (Combining Evidence)

Pathogenic: (1 Very Strong + ≥1 Strong) OR (≥2 Strong) OR (1 Strong + ≥3 Moderate) OR (1 Strong + 2 Moderate + ≥2 Supporting)

Likely Pathogenic: (1 Very Strong + 1 Moderate) OR (1 Strong + 1–2 Moderate) OR (≥3 Supporting Pathogenic criteria)

VUS: Does not meet LP or LB criteria; conflicting or insufficient evidence

Benign/Likely Benign: ≥1 Stand-Alone Benign, or ≥2 Strong Benign, or (1 Strong + 1 Supporting) Benign

Section 3

Pearls/Pitfalls

Key Pearls

VUS ≠ negative — patients and clinicians must understand a VUS cannot be used to guide management; avoid acting on it as if pathogenic.

VUS reclassification rates: ~10–20% of VUS are reclassified annually; recontact protocols are essential.

Gene-specific rules matter — BRCA1/2, TP53, RB1 LOF interpretation differs from MYH7 or SCN5A.

ClinGen gene curation status determines if gene-disease association is gene-specific (e.g., BRCA1-HBOC vs. BRCA1-Fanconi Anemia).

Important Limitation

The ACMG/AMP framework applies to germline variant classification only. Somatic (tumour) variants use separate classification systems (e.g., AMP/ASCO/CAP 2017 Somatic Variant Classification). Do not conflate the two.

Section 4

Next Steps

Clinical Actions

P or LP variant: Disclose to patient with genetic counselling; initiate surveillance/intervention per gene-specific guidelines (e.g., NCCN, ACMG guidelines).

VUS: Counselling to avoid anchoring bias; family segregation studies where possible; schedule reclassification review in 12–24 months.

All positive/LP findings: Offer cascade testing to 1st degree relatives at 50% risk.

LB/Benign: Disclose as non-actionable; reassurance without surveillance modification.

Section 5

Evidence Appraisal

Primary Reference

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Richards S et al. • Genetics in Medicine. 2015;17(5): 405–424

Section 6

Literature

Development

Published in 2015 by a joint ACMG/AMP working group to replace an earlier 3-tier classification (disease-causing, unclassified, polymorphism) that had become inadequate as clinical sequencing expanded. The 2015 framework introduced 28 coded evidence criteria, combining evidence systematically to generate reproducible variant classifications across laboratories.

Evolution

ClinGen has since developed gene-specific variant interpretation guidelines (e.g., BRCA1/2, TP53, RASopathies, Channelopathies) that modify the 2015 framework. Key updates include the Bayesian statistical framework (Tavtigian et al., Genetics in Medicine 2018) formalising evidence weighting as odds of pathogenicity, and the PVS1 null variant decision tree (Abou Tayoun 2018). Over 2 million variants are now classified in ClinVar.

Last Comprehensive Review: 2026

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