ACMG guideline

The table and the module definitions are adapted from the original ACMG guideline publication1.

Overview

ACMG modules	Strong	Supporting	Supporting	Moderate	Strong	Very Strong
Population data	BA1, BS1, BS2			PM2	PS4
Computational and predictive data		BP1, BP4, BP4, BP7,	PP3	PM4, PM5	PS1	PVS1
Functional data	BS3		PP2	PM1	PS3
Segregation data	BS4		PP1
De novo data				PM6	PS2
Allele data		BP2		PM3
Others		BP5, BP6	PP5, PP4

Module definitions and criteria

PVS1

Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.

PS1

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS2

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PS4

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.

PM1

Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.

PM2

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

PM3

For recessive disorders, detected in trans with a pathogenic variant.

PM4

Protein length changes as a result of inframe deletions/insertions in a non-repeat region or stop-loss variants.

PM5

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PM6

Assumed de novo, but without confirmation of paternity and maternity.

PP1

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease

PP2

Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.

PP3

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).

PP4

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

PP5

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

BP1

Missense variant in a gene for which primarily truncating variants are known to cause disease.

BP2

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP3

In-frame deletions/insertions in a repetitive region without a known function.

BP4

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).

BP5

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

BP6

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

BP7

A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.

BS1

Allele frequency is greater than expected for disorder.

BS2

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

BS3

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

BS4

Lack of segregation in affected members of a family.

BA1

Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

References

1

Richards, S. et al. (2015). “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”. Genetics in Medicine 17, 405–423. DOI: 10.1038/gim.2015.30