Variant classification summary

NM_001001890.2:c.1132C>G

RUNX1 · NP_001001890.1:p.(Leu378Val) · NM_001001890.2

GRCh37: chr21:36164662 G>C · GRCh38: chr21:34792365 G>C

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Leu378Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 c.1132C>G (p.Leu378Val, p.L378V) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Uncertain Significance, including an expert-panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2_Supporting under the RUNX1 VCEP threshold of less than or equal to 0.00005.

3

Computational evidence supports a benign effect: REVEL is 0.323, below the RUNX1 BP4 cutoff of less than 0.50, SpliceAI max delta is 0.00, at or below the BP4 cutoff of 0.20, and BayesDel is negative at -0.252196.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 0, which maps to VUS 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
PP4	N/A	The RUNX1 VCEP specifies that PP4 is not applicable because the FPD/AML phenotype is not sufficiently specific for a single genetic etiology.	cspec
PVS1	Not met	This variant is a missense substitution, p.(Leu378Val), and does not fall into the RUNX1 loss-of-function categories used for PVS1. Available evidence does not support a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function effect for this variant.	cspec pvs1_gene_context pvs1_variant_assessment
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed.	cspec
PP5	N/A	The RUNX1 VCEP does not use PP5.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 VCEP PM2_Supporting threshold of less than or equal to 0.00005.	gnomad_v2 gnomad_v4 cspec
BS3	Not assessed	No well-established functional study showing normal RUNX1 function for this variant was identified, so BS3 cannot be assessed.	cspec oncokb
PM4	N/A	PM4 is not applicable because this variant is a missense substitution rather than an in-frame insertion/deletion or stop-loss variant.	cspec
BP4	Met	For this missense variant, REVEL is 0.323, which is below the RUNX1 VCEP BP4 cutoff of less than 0.50, and SpliceAI max delta is 0.00, which is at or below the BP4 cutoff of 0.20. BayesDel is also negative at -0.252196, which is directionally consistent with a non-damaging interpretation.	cspec revel spliceai bayesdel
BP3	N/A	The RUNX1 VCEP does not use BP3.	cspec
PS1	Not met	No previously established pathogenic or likely pathogenic RUNX1 variant producing the same amino acid change was identified in the available expert-panel precedent materials or ClinVar, so PS1 is not met.	cspec clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM6	Not assessed	No assumed de novo occurrences without full parental confirmation were identified for this variant, so PM6 cannot be assessed from the available evidence.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at this amino acid residue was identified in the available expert-panel precedent materials, and SpliceAI does not suggest a splice effect that would change this interpretation. Therefore PM5 is not met from the available evidence.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
BP6	N/A	The RUNX1 VCEP does not use BP6.	cspec
BP7	N/A	BP7 is not applicable because this variant is missense rather than synonymous or intronic.	cspec
BP5	N/A	The RUNX1 VCEP does not use BP5.	cspec
PS4	Not assessed	No proband-level evidence was identified showing this variant in one or more individuals meeting RUNX1 phenotypic criteria, so PS4 cannot be assessed from the available evidence.	cspec clinvar
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec
BS2	N/A	The RUNX1 VCEP does not use BS2.	cspec
PM1	Not met	This missense variant affects Leu378, which is outside the RUNX1 Runt homology domain residue range used for PM1 (residues 89-204) and is not one of the specified PM1_strong residues. Available evidence therefore does not support PM1.	cspec
PP3	Not met	REVEL is 0.323, which is below the RUNX1 VCEP PP3 cutoff of 0.88, and SpliceAI max delta is 0.00, which is below the PP3 splice cutoff of 0.38. BayesDel is negative at -0.252196 and does not provide contradictory computational support. Available computational evidence does not support PP3.	cspec revel spliceai bayesdel
PP2	N/A	The RUNX1 VCEP does not use PP2.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BA1 threshold of at least 0.0015.	gnomad_v2 gnomad_v4 cspec
PS3	Not assessed	No variant-specific functional study showing altered RUNX1 function was identified, so PS3 cannot be assessed from the available evidence.	cspec oncokb
BP1	N/A	The RUNX1 VCEP does not use BP1.	cspec
PM3	N/A	The RUNX1 VCEP does not use PM3.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BS1 frequency range of 0.00015 to 0.0015.	gnomad_v2 gnomad_v4 cspec

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