Variant classification summary

NM_001754.4:c.560C>T

RUNX1 · NP_001745.2:p.(Ala187Val) · NM_001754.4

GRCh37: chr21:36231824 G>A · GRCh38: chr21:34859527 G>A

Gene: RUNX1 Transcript: NM_001754.4

Final call

VUS

PM1 supporting PM2 supporting PP3 supporting

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(Ala187Val)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): Ala187 sits within the RUNX1 Runt Homology Domain (residues 89-204), though not among the 13 hotspot residues.

2

PM2 (Supporting): completely absent from gnomAD v4.1, v2.1, and gnomAD-Canada (MAF 0, below the 0.00005 threshold).

3

PP3 (Supporting): REVEL 0.977 exceeds the 0.88 VCEP threshold for pathogenic missense prediction.

4

Overall: VUS, from 3 supporting points (PM1 + PM2 + PP3) under the MM-VCEP RUNX1 v3.1 rule mapping 0-5 points to Uncertain Significance.

Final determination: Under the ClinGen Myeloid Malignancy VCEP RUNX1 v3.1 point-based framework (Tavtigian 2020), PM1 supporting (+1) + PM2 supporting (+1) + PP3 supporting (+1) totals 3 points, which falls in the Uncertain Significance range (Rule3: >= 0 and <= 5 points).

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	N/A	Not applicable: this is a missense variant with no predicted splicing effect (SpliceAI 0.001), so the null-variant rule does not apply.	cspec spliceai pvs1_variant_assessment
PS1	Not met	Not met: no alternate-nucleotide change at Ala187 has been established as pathogenic, and the only ClinVar record is classified uncertain.	cspec clinvar pm5_candidates
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing for this variant was reported in any source.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific functional study exists; OncoKB reports no reviewed functional evidence for this variant.	cspec oncokb clinvar PMID:28492532
PS4	Not assessed	Not assessed: no proband meeting RUNX1-phenotypic criteria was found for this variant; the single COSMIC hit is somatic.	cspec clinvar gnomad_v2 gnomad_v4 PMID:28492532 PMID:33661592
PM1	Met	Met (supporting): Ala187 lies within the Runt Homology Domain (residues 89-204) but is not one of the 13 hotspot residues.	cspec
PM2	Met	Met (supporting): the variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada (MAF 0, below the 0.00005 threshold).	cspec gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM3	N/A	Not applicable: FPD/AML is autosomal dominant, and PM3 applies only to recessive disorders.	cspec
PM4	N/A	Not applicable: p.Ala187Val is a single amino acid substitution with no change in protein length.	cspec
PM5	Not met	Not met: no pathogenic variant at residue 187 exists as a comparator, and PM1 application independently bars PM5.	cspec pm5_candidates spliceai
PM6	Not assessed	Not assessed: no assumed de novo occurrences of this variant are reported in any source.	cspec clinvar
PP1	Not assessed	Not assessed: no pedigree, segregation, or meiosis data for this variant is available.	cspec clinvar
PP2	N/A	Not applicable: RUNX1's missense constraint z-score (2.48 ExAC) is below the 3.09 cutoff required by the VCEP.	cspec
PP3	Met	Met (supporting): REVEL score 0.977 exceeds the 0.88 VCEP threshold for pathogenic missense prediction.	cspec revel spliceai
PP4	N/A	Not applicable: the FPD/AML phenotype is too unspecific to satisfy the PP4 rule under the VCEP.	cspec
PP5	Not met	Not met: the only expert-panel ClinVar classification for this exact variant is Uncertain Significance, not Pathogenic.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD (MAF 0), far below the 0.0015 BA1 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 band in gnomAD.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	Not applicable: the VCEP excludes BS2 because FPD/AML has incomplete penetrance and late average onset (33 years).	cspec
BS3	Not assessed	Not assessed: no assay demonstrates normal transactivation (80-115% of wild-type) for this variant.	cspec oncokb clinvar PMID:28492532
BS4	Not assessed	Not assessed: no genotype-negative, phenotype-positive family members or informative meioses were reported.	cspec clinvar
BP1	N/A	Not applicable: both truncating and missense RUNX1 variants cause FPD/AML, so missense cannot be assumed benign.	cspec
BP2	Not met	Not met: no homozygous, trans, or cis observations of this variant with a pathogenic allele were reported.	cspec gnomad_v2 gnomad_v4 clinvar
BP3	N/A	Not applicable: RUNX1 contains no repetitive region without known function, and this is not an in-frame indel.	cspec
BP4	Not met	Not met: REVEL 0.977 fails the <0.50 requirement, so the missense benign-prediction rule is not satisfied.	cspec revel spliceai
BP5	N/A	Not applicable: the VCEP excludes BP5 because patients may rarely carry two pathogenic hematologic-malignancy variants.	cspec
BP6	Not met	Not met: the only expert-panel ClinVar classification for this exact variant is Uncertain Significance, not Benign.	cspec clinvar
BP7	N/A	Not applicable: this is a missense variant, while BP7 covers only synonymous and intronic variants.	cspec

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