NM_001001890.2:c.556C>G

RUNX1 · NP_001001890.1:p.(Gln186Glu) · NM_001001890.2

GRCh37: chr21:36206875 G>C · GRCh38: chr21:34834578 G>C

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM2 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Gln186Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The RUNX1 c.556C>G (p.Gln186Glu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen Myeloid Malignancy Variant Curation Expert Panel classified the canonical transcript change NM_001754.5:c.637C>G (p.Gln213Glu) as uncertain significance.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting RUNX1 PM2_Supporting because the observed allele frequency is 0 and therefore below the VCEP threshold of 0.00005.

Computational evidence does not meet the RUNX1 thresholds for either PP3 or BP4: SpliceAI predicts no significant splice effect with a max delta score of 0.01, REVEL is 0.59, and BayesDel is 0.0862396.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 1, 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
PVS1	N/A	This is a missense variant with no predicted splice disruption, so it does not fit the RUNX1 PVS1 loss-of-function framework for null or splice-disrupting variants.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No previously established pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available ClinVar or RUNX1 VCEP materials, so PS1 was not applied.	clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	clinvar
PS3	Not assessed	No variant-specific functional study showing abnormal RUNX1 function was identified in the available curated sources, so PS3 was not applied.	oncokb clinvar cspec
PS4	Not assessed	No case series or proband count was identified showing enrichment of this variant in individuals meeting RUNX1-associated phenotype criteria, so PS4 was not applied.	clinvar cspec
PM1	Not met	Under the RUNX1 VCEP default transcript, ClinVar maps this variant to NM_001754.5:c.637C>G (p.Gln213Glu). The RUNX1 PM1 region is limited to residues 89-204 in the Runt homology domain, and p.Gln213 is outside that range; Cancer Hotspots also did not identify a hotspot signal at this residue.	clinvar cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not used in the RUNX1 VCEP framework for this disorder context.	cspec
PM4	N/A	This is not an in-frame insertion/deletion or stop-loss variant, so PM4 is not applicable.	cspec
PM5	Not assessed	SpliceAI is low enough that a splice effect would not block PM5 consideration, but no previously established pathogenic or likely pathogenic different missense change at this residue was identified in the available ClinVar or RUNX1 VCEP materials, so PM5 was not applied.	clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results spliceai cspec
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.	clinvar cspec
PP2	N/A	PP2 is not used in the RUNX1 VCEP framework.	cspec
PP3	Not met	For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38. This variant has REVEL 0.59, BayesDel 0.0862396, and SpliceAI max delta 0.01, so the available computational evidence does not meet the RUNX1 PP3 threshold.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in the RUNX1 VCEP framework because the associated phenotype is not sufficiently specific for a single genetic etiology.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not reach the RUNX1 BA1 threshold of at least 0.0015.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not fall within the RUNX1 BS1 frequency range of 0.00015 to 0.0015.	gnomad_v2 gnomad_v4 cspec
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No variant-specific functional study showing normal RUNX1 function was identified, so BS3 was not applied.	oncokb clinvar cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not applied.	clinvar cspec
BP1	N/A	BP1 is not used in the RUNX1 VCEP framework.	cspec
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 was not applied.	clinvar cspec
BP3	N/A	BP3 is not used in the RUNX1 VCEP framework.	cspec
BP4	Not met	For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20. SpliceAI is low at 0.01, but REVEL is 0.59, so the VCEP BP4 rule is not met. BayesDel is available at 0.0862396, but the RUNX1 VCEP BP4 rule is based on REVEL and SpliceAI.	revel bayesdel spliceai cspec
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	N/A	BP6 is not used in the RUNX1 VCEP framework.	cspec
BP7	N/A	This is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable.	cspec

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