Table 1.
Summary of the adapted ACMG/AMP pathogenic and benign criteria.
| Pathogenic Criteria | Combination of Criteria Needed to Meet Classification | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Rule | Specification Type | Rule Description | Pathogenic | Likely Pathogenic | |||||||
| VS | PVS1 | Removed | Null variant in gene with established LOF as disease mechanism | ||||||||
| STRONG | PS1 | No change | Different nucleotide change (same amino acid) as a previously established pathogenic variant | 2 | 1 | 1 | 1 | 1 | |||
| PS2 | Disease/gene | De novo (paternity confirmed) in a patient with disease and no family history | |||||||||
| PS3 | Disease/gene | Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product | |||||||||
| PS4 | Disease/gene | Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls -OR- Variant identified in ≥15 probands with consistent phenotypes | |||||||||
| PP1_Strong | Modif. Strength | Variant segregates with ≥7 meioses | |||||||||
| MODERATE | PM1 | Disease/gene | Hotspot/est. functional domain (amino acids 181–937) without benign variation | 3 | 2 | 1 | 1 | 3 | 2 | ||
| PM2 | Disease/gene | Absent/extremely rare (<0.004%) from large population studies | |||||||||
| PM3 | Removed | Detected in trans with a pathogenic variant (recessive) | |||||||||
| PM4 | No change | Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants | |||||||||
| PM5 | No change | Missense change at an amino acid residue where a different missense change previously established as pathogenic | |||||||||
| PM6 | Disease/gene | Confirmed de novo without confirmation of paternity | |||||||||
| PVS1_Moderate | Modif. Strength | Null variant in gene with evidence supporting LOF as disease mechanism | |||||||||
| PS4_Moderate | Modif. Strength | Variant identified in ≥6 probands with consistent phenotypes | |||||||||
| PP1_Moderate | Modif. Strength | Variant segregates in ≥5 meioses | |||||||||
| SUPPORTING | PP1 | Disease/gene | Variant segregates in ≥3 meioses | 2 | 4 | 2 | 2 | ||||
| PP2 | Removed | Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease | |||||||||
| PP3 | No change | Multiple lines of computational evidence support a deleterious effect on the gene or gene product | |||||||||
| PP4 | Removed | Phenotype specific for disease with single genetic etiology | |||||||||
| PP5 | Removed | Reputable source reports as pathogenic | |||||||||
| PS4_Supporting | Modif. strength | Variant identified in ≥2 probands with consistent phenotypes | |||||||||
| Benign Criteria | Combination of Criteria Needed to Meet Classification | ||||||
|---|---|---|---|---|---|---|---|
| Rule | Specification Type | Rule Description | Benign | Likely Benign | |||
| SA | BA1 | Disease/gene | Allele frequency is ≥0.1% based on the filtering allele frequency (FAF) in ExAC | 1 | |||
| STRONG | BS1 | Disease/gene | Allele frequency is ≥0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information | 2 | 1 | ||
| BS2 | Removed | Observed in healthy adult with full penetrance expected at an early age | |||||
| BS3 | No change | Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing | |||||
| BS4 | Disease/gene | Non-segregation in affected members of a family | |||||
| SUPPORTING | BP1 | Removed | Missense variant in gene where only LOF causes disease | 2 | |||
| BP2 | Disease/gene | Observed as comp het (in trans) or double het in genes with overlapping function (e.g. sarcomere genes) without increased disease severity -OR- Observed in cis with a pathogenic variant in any inheritance pattern | |||||
| BP3 | Removed | In-frame deletions/insertions in a repetitive region without a known function | |||||
| BP4 | No change | Multiple lines of computational evidence suggest no impact on gene or gene product | |||||
| BP5 | Disease/gene | Variant found in a case with an alternate molecular basis for disease | |||||
| BP6 | Removed | Reputable source reports as benign | |||||
| BP7 | No change | A 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 | |||||
VS = Very Strong. SA = Stand alone. Removed - not applicable to MYH7-associated disease. Modif. strength: Modified rule strength. Numbers under each classification refer to the number of rules with that strength required to classify the variant as its header category. Example: A likely pathogenic classification may be made with 1 piece of strong and 2 pieces of supporting evidence.