Page 34 - Haematologica April 2020

D. Wu et al.
876
haematologica | 2020; 105(4)
continued from the previous page
ACMG/ AMP CC
Original ACMG/AMP rule summary
Specification
Stand alone
Very strong
Strong
Moderate
Supporting
Comments
PP1
Disease- strength
na
na
≥ 7 meioses observed within one or across multiple families.
5 or 6 meioses observed within one or across multiple families.
3 or 4 meioses observed within one or
(1) Affected individuals show at least one of the RUNX1- specific phenotypic criteria. (2) Only genotype and phenotype positive individuals and obligate carriers are counted. (3) Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family.
PP2
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
na
Missense constraint z-score for RUNX1 is <3.09.
PP3
Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
General rec
na
na
na
na
Per original ACMG/AMP guidelines.
(1) PP3 should be applied for missense variants with a REVEL score of >0.75 (2) PP3 should be applied for missense or synonymous variants if the variant alters the last three bases of an exon preceding a donor splice site or the first three bases of an exon following a splice acceptor site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site. (3)
PP3 should also be applied for intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for splice donor sites or -3 to -5 for splice acceptor sites for which the predicted decrease in the score is at least 75% (measured by both MES and SSF) regardless of the predicted creation/presence of a putative cryptic splice site. (4) PP3 cannot be applied for canonical splice site variants.
PP4
Patient’s phenotype or family
history is highly specific for
a disease with a single genetic etiology.
na
FPD/AML does not exhibit a highly specific phenotype and there is substantial genetic heterogeneity.
PP5
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent analysis.
na
According to SVI recommendations.
Co-segregation with disease
in multiple affected family members.specific,
Adapted from Table 1 of Luo and Feurstein et al.18 ACMG: American College of Medical Genetics; AMP: Association for Molecular Pathology; CC: criteria code; , ESP: Exome Sequencing Project; 1000G: 1000 Genome project; ExAc: Exome Aggregation Consortium; MAF: minor allele frequency;na:not applicable;FPD/AML:familial platelet disorder with predisposition to acute myeloid leukemia;rec:recommendation;SSF:splice site finder;MES:MaxEntScan;SVI:ClinGen SequenceVariant InterpretationWorking Group; LOF:loss-of-function; SNV:single-nucleotide variant; CNV:copy number variant;NMD:nonsense-mediated decay; AA:amino acid;MM-VCEP:Myeloid MalignancyVariant Curation Expert Panel;wt:wildtype;EMSA:electrophoretic mobility shift assay;IP:immunoprecipitation; FRET:fluorescence resonance energy transfer; IF: immunofluorescence;WB: western blot; gnomAD: Genome Aggregation Database; RHD: Runt homology domain.
phenotype.
phenotype.
across multiple families.