Variant classification summary

NM_001754.4:c.707dupT

RUNX1 · NP_001745.2:p.(Met236IlefsTer25) · NM_001754.4

GRCh37: chr21:36206804 C>CA · GRCh38: chr21:34834507 C>CA

Gene: RUNX1 Transcript: NM_001754.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(Met236IlefsTer25)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): out-of-frame frameshift (p.Met236IlefsTer25) predicted to trigger nonsense-mediated decay, an established RUNX1 disease mechanism.

2

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with MAF 0 versus the <=0.00005 threshold.

3

PM5 (Supporting): frameshift downstream of c.98 with no splicing impact (SpliceAI max delta 0.036, <=0.20).

4

These criteria total 10 points (PVS1 very strong, PM2 and PM5 supporting), meeting Rule 1 (>=10) and classifying the variant as Pathogenic.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met (Very Strong): out-of-frame duplication creates a premature stop codon predicted to trigger nonsense-mediated decay, the established RUNX1 loss-of-function mechanism.	cspec pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework spliceai
PS1	N/A	Not applicable: PS1 applies only to missense variants, and this frameshift has no alternate nucleotide change producing the same protein.	cspec clinvar
PS2	Not assessed	Not assessed: no proband genotype, parental testing, or family history data were available for this variant.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific functional assay data (transactivation or secondary assays) were available.	cspec oncokb
PS4	Not assessed	Not assessed: no proband observations were found in ClinVar, gnomAD, COSMIC, or the reviewed literature.	cspec
PM1	Not met	Not met: p.Met236 lies outside the Runt Homology Domain (amino acids 89-204) to which PM1 is restricted.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with MAF 0 versus the <=0.00005 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is reserved for recessive disorders, and RUNX1 FPD/AML is autosomal dominant.	cspec
PM4	N/A	Not applicable: PM4 covers only in-frame indels and stop-loss variants; this is an out-of-frame frameshift.	cspec
PM5	Met	Met (Supporting): frameshift downstream of c.98 with SpliceAI max delta 0.036 (<=0.20), indicating no splicing impact.	cspec spliceai pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrences were reported; no parental testing data or ClinVar submissions exist.	cspec clinvar
PP1	Not assessed	Not assessed: no pedigree or segregation data were available for this variant.	cspec clinvar
PP2	N/A	Not applicable: RUNX1 missense constraint z-score 2.48 is below the 3.09 cutoff, and this variant is a frameshift.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.036 versus the >=0.38 threshold; no calibrated predictor scores support pathogenicity.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
PP4	N/A	Not applicable: phenotype specificity is not a scored criterion in the MM-VCEP RUNX1 specification.	cspec
PP5	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel classification exists to support PP5.	cspec clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
BA1	Not met	Not met: absent from all gnomAD datasets, with MAF 0 versus the >=0.0015 stand-alone threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: MAF 0 is below the 0.00015 lower bound of the BS1 range.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	Not applicable: FPD/AML has incomplete penetrance and late average onset, so healthy-adult carriers are not benign evidence.	cspec
BS3	Not assessed	Not assessed: no functional studies demonstrating normal transactivation or function were available.	cspec oncokb
BS4	Not assessed	Not assessed: no informative meioses showing lack of segregation were reported.	cspec clinvar
BP1	N/A	Not applicable: both truncating and missense RUNX1 variants cause FPD/AML, so the criterion's premise does not hold.	cspec
BP2	Not met	Not met: no trans, cis, or homozygous observations of the variant were found.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	Not applicable: RUNX1 has no repetitive region without known function.	cspec
BP4	N/A	Not applicable: BP4 covers only missense and synonymous/intronic variants; this is a frameshift duplication.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP5	N/A	Not applicable: the alternative-molecular-basis criterion is not part of the MM-VCEP RUNX1 specification.	cspec
BP6	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel benign classification exists to support BP6.	cspec clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP7	N/A	Not applicable: BP7 covers only synonymous and intronic variants; this is a coding frameshift.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results

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