Variant classification summary

NM_001754.4:c.1252A>T

RUNX1 · NP_001745.2:p.(Met418Leu) · NM_001754.4

GRCh37: chr21:36164623 T>A · GRCh38: chr21:34792326 T>A

Gene: RUNX1 Transcript: NM_001754.4

Final call

Benign

BA1 stand-alone benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(Met418Leu)

gnomAD AF

0.00140621707139944 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001754.4:c.1252A>T (p.Met418Leu) in RUNX1 is classified as Benign per the ClinGen Myeloid Malignancy VCEP RUNX1 specifications v3.1.

2

BA1 is met at stand-alone benign strength: the variant has an allele frequency of 0.507% in the East Asian population (gnomAD v4.1, 119/23,476 alleles, 0 homozygotes), exceeding the MM-VCEP BA1 threshold of ≥0.15% with ≥2,000 alleles tested and ≥5 variant alleles.

3

BP4 is met at supporting benign strength: REVEL score 0.219 (<0.50) and SpliceAI max delta 0.00 (≤0.20) indicate a benign in silico prediction per MM-VCEP thresholds.

4

BP6 is met at supporting benign strength: the ClinGen Myeloid Malignancy VCEP expert panel (3-star review) classified this variant as Benign (ClinVar ID 1703790).

5

The variant is a missense change (p.Met418Leu) in the C-terminal region of RUNX1, outside the Runt homology domain (residues 89–204). No pathogenic criteria are met.

6

Point-based classification (Tavtigian 2020): BA1 (-8) + BP4 (-1) + BP6 (-1) = −10 points, meeting the Benign threshold (≤−7).

Final determination: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework yields a total score of -10, which maps to Benign under the specified Tavtigian-style ranges.

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	This is a missense variant (c.1252A>T, p.Met418Leu), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is applicable only to null variants per the RUNX1 MM-VCEP PVS1 decision tree.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	No evidence that the same amino acid change (p.Met418Leu) has been previously established as pathogenic or likely pathogenic via a different nucleotide change.	cspec clinvar
PS2	Not met	No proven de novo occurrences (with maternity and paternity confirmed) have been reported for this variant in patients with FPD/AML phenotype.	cspec clinvar
PS3	Not met	No variant-specific functional data (transactivation assays or secondary functional assays) are available for p.Met418Leu. OncoKB reports unknown oncogenic effect with no curated functional evidence.	oncokb cspec
PS4	Not met	No probands meeting RUNX1-phenotypic criteria have been specifically reported for this variant. The variant is present at population frequency in gnomAD, inconsistent with a highly penetrant pathogenic variant.	gnomad_v4 cspec clinvar
PS5	N/A	PS5 has been subsumed by PP5 in the ACMG/AMP 2015 framework. The MM-VCEP designates PP5 as not applicable for RUNX1, and the ClinVar expert panel classification is Benign (not pathogenic).	cspec
PM1	Not met	Residue 418 (Met418) lies in the C-terminal region of RUNX1, well outside the Runt homology domain (RHD, residues 89–204) for which the MM-VCEP defines PM1 applicability. PM1_strong is limited to 13 specific RHD residues; PM1_supporting covers residues 89–204.	cspec
PM2	Not met	The variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.004329 (0.43%) and an East Asian AF of 0.005069 (0.51%), far exceeding the MM-VCEP PM2_supporting threshold of ≤0.00005 (0.005%).	gnomad_v4 cspec
PM5	Not met	No different missense changes at residue 418 have been established as pathogenic or likely pathogenic in ClinVar. PM5 requires a different missense change at the same residue with a prior pathogenic/likely pathogenic classification.	cspec clinvar pm5_candidates
PM6	Not met	No assumed de novo occurrences (without confirmation of maternity and paternity) have been reported for this variant in patients with FPD/AML phenotype. MM-VCEP requires ≥2 assumed de novo for PM6_supporting.	cspec clinvar
PP1	Not met	No co-segregation data are available. MM-VCEP requires ≥3 meioses for PP1 at supporting level.	cspec
PP2	N/A	PP2 (missense in a gene with low rate of benign missense variation) is designated as Not Applicable by the MM-VCEP for RUNX1.	cspec
PP3	Not met	REVEL score is 0.219 (threshold ≥0.88 required) and SpliceAI max delta is 0.00 (threshold ≥0.38 required). Neither in silico predictor meets the MM-VCEP PP3 threshold for missense variants.	revel spliceai cspec
PP4	N/A	PP4 (phenotype highly specific for single genetic etiology) is designated as Not Applicable by the MM-VCEP because the FPD/AML phenotype is nonspecific and can be caused by multiple inherited predisposition syndromes.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the MM-VCEP per ClinGen SVI VCEP Review Committee recommendation. The ClinVar expert panel classification for this variant is Benign, not pathogenic.	cspec clinvar
BA1	Met	The variant has a minor allele frequency of 0.50690% (119/23,476 alleles) in the East Asian population in gnomAD v4.1, exceeding the MM-VCEP BA1 threshold of ≥0.15% in a general continental population dataset with ≥2,000 alleles and ≥5 variant alleles. This alone is sufficient to classify the variant as benign.	gnomad_v4 cspec
BS1	Not met	BS1 is superseded by BA1. The variant's East Asian AF of 0.50690% exceeds the upper bound of the BS1 range (0.015%–0.15%), meeting the more stringent BA1 stand-alone benign criterion instead.	gnomad_v4 cspec
BS2	N/A	BS2 (observed in healthy adult) is designated as Not Applicable by the MM-VCEP for RUNX1.	cspec
BS3	Not met	No functional data demonstrating normal transactivation activity (80–115% of wild-type) are available for this variant. MM-VCEP BS3 requires transactivation assay data showing normal function.	cspec oncokb
BS4	Not met	No non-segregation data are available. MM-VCEP BS4 requires observation in ≥2 informative meioses where the variant does not segregate with disease.	cspec
BP1	N/A	BP1 (missense variant in gene where primarily truncating variants cause disease) is designated as Not Applicable by the MM-VCEP for RUNX1.	cspec
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant. No homozygous observations have been reported in FPD/AML patients.	cspec gnomad_v4
BP4	Met	REVEL score is 0.219 (<0.50) and SpliceAI max delta score is 0.00 (≤0.20), meeting the MM-VCEP BP4 threshold for missense variants. Multiple in silico predictors support a benign interpretation.	revel spliceai bayesdel cspec
BP5	N/A	BP5 (variant found in case with alternate molecular basis for disease) is designated as Not Applicable by the MM-VCEP for RUNX1.	cspec
BP6	Met	Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Benign.	clinvar
BP7	N/A	BP7 (synonymous or intronic variant with no predicted splice impact) applies only to synonymous and intronic variants per MM-VCEP specification. This is a missense variant (c.1252A>T, p.Met418Leu).	cspec

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