Table 1 Utilization of ACMG criteria and knowledgebase in PathoMAN variant curation
From: Toward automation of germline variant curation in clinical cancer genetics
Category | ACMG criteria | Utilization of ACMG criteria in PathoMAN’s variant classification |
|---|---|---|
Literature and other sources | PVS1 | Tier 1 variants (frameshift, truncating, essential splice, and initiation codon) in curated list of tumor suppressor genes and cancer predisposition genes and not in their last exon |
Public databases | PS1 | Missense variant (HGVS protein change) in ClinVar with review status ≥2 irrespective of the genomic alternative allele |
De novo data | PS2 | User input |
Public databases; functional data | PS3 | Variant in list of pathogenic variants knowledgebase aggregated from literature with functional evidence, public database with loss of function reports, tier 1 variants in ClinVar reported with review status ≥2 and missense variants reported by ENIGMA |
Population frequency data | PS4 | Fisher’s case–control test odds ratio >3 and Pval <0.05 against ExAC noTCGA and gnomAD population of interest (applies to variants with BA1, BS1, BS2, and PM2 equal to 0) |
Public databases | PM1 | Amino acid residue in protein’s domain or residue for signaling or protein–protein interaction or in active site from Uniprot |
Population frequency data | PM2 | Variant absent from ExAC noTCGA or gnomAD |
Allelic/genotypic data | PM3 | Not used in the current version |
Public databases | PM4 | In-frame ins/del or stoploss in a nonrepetitive region from University of California–Santa Cruz (UCSC) Genome Browser |
Public databases | PM5 | Missense variant in ClinVar with review status ≥2 irrespective of the alternative amino acid change at the same position as that of the reported pathogenic variant in ClinVar |
De novo data | PM6 | User input |
Segregation data | PP1 | User input |
Public databases | PP2 | Variant in gene with significant pathogenic missense burden in ClinVar |
Genomic annotation and computational predictive data | PP3 | In silico predictors agree on pathogenicity or deleteriousness of the variant |
Other (disease specific) | PP4 | Not used in the current version |
Public databases | PP5 | Variant in ClinVar with review status <2 and pathogenic without conflicts |
Population frequency data | BA1 | Variant seen in ExAC noTCGA or gnomAD with AF >5% |
Population frequency data | BS1 | Variant seen in ExAC noTCGA or gnomAD with AF between 1% and 5% |
Population frequency data | BS2 | Variant seen in ExAC noTCGA or gnomAD general population in homozygous form |
Public databases; functional data | BS3 | Variant in list of benign variants knowledgebase aggregated from literature with functional evidence, public database with loss of function reports, tier 1 variants in ClinVar reported with review status ≥ 2 and missense variants reported by ENIGMA |
De novo data | BS4 | User input |
Public databases | BP1 | Variant in gene with significant benign missense burden in ClinVar |
Allelic/genotypic data | BP2 | Not used in the current version |
Public databases | BP3 | In-frame ins/del or stop loss in a repetitive region from UCSC Genome Browser |
Genomic annotation and Computational predictive data | BP4 | In silico predictors agree on benignity or tolerance of the variant |
Other (disease specific) | BP5 | Not used in the current version |
Public databases | BP6 | Variant in ClinVar with review status <2 and benign without conflicts |
Genomic annotation and computational predictive data | BP7 | Synonymous variant with dbscSNV adaptive boosting and random forest score <0.6 |
