What is ACMG/AMP variant classification?

The ACMG/AMP 2015 guidelines (Richards et al., Genetics in Medicine) are the international reference standard for classifying germline genetic variants into 5 tiers: Pathogenic, Likely Pathogenic, Variant of Uncertain Significance (VUS), Likely Benign, and Benign. Classification is based on combining 28 weighted evidence criteria (PVS1, PS1–PS4, PM1–PM6, PP1–PP5, BA1, BS1–BS4, BP1–BP7).

What is the difference between NGSDiag V1 and NGSDiag V2?

NGSDiag is a French adaptation of the ACMG/AMP guidelines. V1 applies the original 28 criteria with fixed weights. V2 introduces modulated evidence weighting following ClinGen SVI recommendations: several criteria (PVS1, PS2, PS4, PM3, PM6, PP1, PP4) can be applied at different strength levels. V2 also removes PP5 and BP6, and renames PP1 to P1 and PP4 to P4.

What is the ABC classification system?

The ABC system (Houge et al., ESHG 2021) classifies variants on two independent axes: Grade A (functional/molecular evidence, 6 levels from A0 to A5) and Grade B (clinical/phenotypic evidence, 6 levels from B0 to B5). These are combined in a 2D matrix to produce a final class from A (pathogenic, high penetrance) to F (discordant gene) or 0 (insufficient data). It is complementary to the ACMG/AMP framework.

What is the PVS1 criterion?

PVS1 (Very Strong Pathogenic) applies to loss-of-function variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, exon deletion) in genes where loss-of-function is a known disease mechanism. NMD must be predicted and the affected exon constitutive. In NGSDiag V2, PVS1 can be downgraded to PVS1_fort (Strong), PVS1_moyen (Moderate), or PVS1_faible (Supporting) depending on NMD confidence and proportion of protein lost.

How are ACMG criteria combined to reach a classification?

Pathogenic requires: 1 PVS + 1 PS, or 1 PVS + 2 PM, or 2 PS, or 1 PS + 3 PM, among other combinations. Likely Pathogenic: 1 PVS alone, or 1 PS + 1 PM, or 3 PM, among others. Benign: 1 BA1 or 2 BS. Likely Benign: 1 BS + 1 BP or 2 BP. VUS when no combination is met or evidence is conflicting.

What in silico tools are used for PP3 and BP4 criteria?

PP3 (deleterious) and BP4 (benign) rely on concordant in silico predictions from tools such as SIFT (deleterious if ≤0.05), PolyPhen-2 (probably damaging if >0.85), REVEL (pathogenic if >0.5), CADD (deleterious if >20–30), AlphaMissense (pathogenic if >0.564), and SpliceAI (impact if >0.2, strong if >0.8). PP3 and BP4 are mutually exclusive and should never be applied together.

Is ACMG-Academy free to use?

Yes, ACMG-Academy is completely free. It requires no registration or login. It provides interactive decision trees, a clinical case simulator with real-world examples, and guides for ACMG/AMP V1, NGSDiag V2, and the ABC classification system.

ACMG-Academy - Genetic Variant Classification according to ACMG/AMP

Learn to classify
genetic variants

Master ACMG/AMP classification and the ABC System (ESHG/Houge et al.) through interactive guides and clinical cases. Available in French and English.

The 5 ACMG Classes of Genetic Variants

Every variant identified through sequencing is classified according to its presumed clinical and biological impact.

Pathogenic

Established disease cause

Reported

Likely Pathogenic

Very likely causal

Reported

VUS

Uncertain Significance

Inconclusive evidence

Not reported

Likely Benign

Very likely neutral

Not reported

Benign

Neutral polymorphism

Not reported

Classification per ACMG/AMP guidelines (Richards et al. 2015) — P and LP variants are communicated to the patient and referring physician as they have direct clinical implications. VUS, LB, and B variants are generally not reported.

Based on official guidelines

ACMG-Academy is based on the ACMG/AMP 2015 guidelines and the two-dimensional ABC classification (ESHG/Houge et al. 2021) for genetic variant interpretation.

International reference: Richards S, Aziz N, Bale S, et al. 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. Genet Med. 2015;17(5):405-424.

doi:10.1038/gim.2015.30

ESHG Recommendation — ABC System: Houge G, et al. Stepwise ABC system for classification of any type of genetic variant. Eur J Hum Genet. 2022;30(4):461–470.

doi.org/10.1038/s41431-021-00903-z

French guidelines — NGS-Diag V1: ANPGM. Best practices for the interpretation of sequence variants (NGS-Diag). BP-NGSDiag_001_Interpretation_Variants_v1. 2019.

anpgm.fr

French guidelines — NGS-Diag V2: ANPGM. Best practices for the interpretation of sequence variants (NGS-Diag). BP-NGSDiag_001_Interpretation_Variants_v2. 2021.

anpgm.fr

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The 5 ACMG Classes of Genetic Variants

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