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Class | Classification | Category | Criteria |
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5 | Pathogenic | A 1 needed (stand-alone) | (i) Alterations resulting in premature truncation (e.g., reading frame shift, nonsense) |
(ii) Other ACMG-defined mutations (i.e., initiation codon or gross deletion) |
(iii) Strong segregation with disease (LOD >3 = >10 meioses) |
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5 | Pathogenic | B 4 needed (strong) | (i) Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family (ii) Significant disease association in appropriately sized case-control study(ies) |
(iii) Being detected in individuals satisfying established diagnostic criteria for classic disease without a clear mutation |
(iv) Last nucleotide of exon |
(v) Good segregation with disease (LOD 1.5–3 = 5–9 meioses) |
(vi) Deficient protein function in appropriate functional assay(s) |
(vii) Functionally validated splicing mutation |
(viii) Well-characterized mutation at the same position |
(ix) Other strong data supporting pathogenic classification (e.g., structural) |
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4 | Likely pathogenic | 1 needed | (i) Alterations at the canonical donor/acceptor sites (± 1, 2) without another strong (B-level) evidence supporting pathogenicity |
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4 | Likely pathogenic | C 4 needed (supportive) | (i) Rarity in general population databases (dbSNP, ESP, 1000 Genomes, ExAC) |
(ii) In silico models in agreement (deleterious) and/or completely conserved position in appropriate species |
(iii) Moderate segregation with disease (at least 3 informative meioses) for rare diseases |
(iv) Other data supporting pathogenic classification (e.g., structural) |
3 of B |
2 of B and at least 1 of C |
1 of B and at least 3 of C |
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3 | VUS | Insufficient or conflicting evidence |
Gross duplications without strong evidence for pathogenic or benign |
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3 | Likely benign | D 1 needed (strong) | (i) Intronic alteration with no splicing impact by RT-PCR analysis or another splicing assay (ii) Other strong data supporting benign classification |
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3 | Likely benign | E 2 needed (supportive) | (i) Cooccurrences with mutations in the same gene (phase unknown) |
(ii) Cooccurrences with mutations in other high penetrant genes that clearly explain a proband’s phenotype |
(iii) Subpopulation frequency in support of benign classification |
(iv) Intact protein function observed in appropriate functional assay(s) |
(v) In silico models in agreement (benign) |
(vi) Not segregating with disease in family study (genes with incomplete penetrance) |
(vii) No disease association in small case-control study |
(viii) Other data supporting benign classification |
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1 | Benign | F 1 needed (stand-alone) | (i) General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance |
(ii) Not segregating with disease in family study (genes with complete penetrance) |
(iii) Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance |
(iv) Being seen in trans with a mutation or in homozygous state in individuals without severe disease for that gene |
(v) No disease association in appropriately sized case-control study(ies) |
1 of D and at least 2 of E |
2 or more of D |
>3 of E w/o conflicting data |
>4 of E w/conflicting data |
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