Variant classification summary

NM_001001890.2:c.590G>A

RUNX1 · NP_001001890.1:p.(Arg197Gln) · NM_001001890.2

GRCh37: chr21:36206841 C>T · GRCh38: chr21:34834544 C>T

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Arg197Gln)

gnomAD AF

2.481928458412186e-06 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 c.590G>A (p.Arg197Gln) 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 VCEP.

2

This variant is present at very low frequency in population databases, with gnomAD v4.1 showing 4/1611650 alleles and a grpmax FAF of 6.8e-07, which is below the RUNX1 PM2_Supporting threshold of 5.0e-05.

3

No reviewed variant-specific functional evidence demonstrating either abnormal or normal RUNX1 function was identified, so the current evidence does not support PS3 or BS3.

4

This missense change affects Arg197 within the RUNX1 Runt homology domain, supporting PM1_Supporting under the RUNX1 VCEP, but computational evidence does not meet PP3 or BP4 because REVEL is 0.702, SpliceAI is 0.01, and the RUNX1 thresholds are REVEL at least 0.88 for PP3 and less than 0.50 with SpliceAI at most 0.20 for BP4.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 2, 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	Not met	This variant is a missense substitution, not a predicted loss-of-function variant, and available evidence does not indicate a canonical splice-site or other null effect that would support PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic or likely pathogenic variant causing the same amino acid change was identified in the reviewed ClinVar evidence, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	cspec clinvar
PS3	Not assessed	No validated variant-specific functional assay showing abnormal RUNX1 activity was identified, so PS3 cannot be applied from the current evidence.	cspec oncokb
PS4	Not assessed	This variant has been reported in ClinVar, but no verified count of unrelated probands meeting RUNX1 phenotypic criteria was identified to support PS4.	cspec clinvar
PM1	Met	This missense variant affects Arg197, which lies within the RUNX1 Runt homology domain residue range 89-204 defined by the RUNX1 VCEP for PM1_Supporting. The residue is within the critical DNA-binding domain but is not one of the 13 residues specified for PM1_Strong.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM2	Met	This variant is present at very low frequency in population databases. In gnomAD v4.1, the grpmax FAF is 6.8e-07, which is below the RUNX1 PM2_Supporting threshold of 5.0e-05, with 4/1611650 alleles observed overall and more than 2000 alleles assessed; gnomAD v2.1 likewise shows only 1/250946 alleles.	cspec gnomad_v4 gnomad_v2
PM3	N/A	PM3 is not applicable in the RUNX1 germline dominant framework used for this variant.	cspec
PM4	N/A	This variant is a missense substitution and not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply.	cspec
PM5	Not met	No different missense variant at the same residue was verified as pathogenic or likely pathogenic in the reviewed evidence, so PM5 is not met.	clinvar cspec
PM6	Not assessed	No assumed de novo occurrences without full parental confirmation were identified for this variant.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is not applicable in the RUNX1 VCEP framework.	cspec
PP3	Not met	Available computational evidence does not meet the RUNX1 PP3 threshold. REVEL is 0.702, which is below the PP3 cutoff of 0.88, and SpliceAI max delta score is 0.01, which is below the splice threshold of 0.38. BayesDel is 0.137586, but the RUNX1 VCEP computational rule is based on REVEL and SpliceAI.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in the RUNX1 VCEP framework because the associated phenotype is not considered sufficiently specific for this rule.	cspec
PP5	N/A	PP5 is not used in this framework.	cspec
BA1	Not met	Population frequency is far below the RUNX1 BA1 threshold. In gnomAD v4.1, total AF is 2.48e-06 and grpmax FAF is 6.8e-07, both below the BA1 threshold of 0.0015.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Population frequency does not reach the RUNX1 BS1 range. The highest observed gnomAD v4.1 population AF is 2.23264e-05 in East Asian samples, which is below the BS1 lower threshold of 0.00015.	cspec gnomad_v4 gnomad_v2
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No validated variant-specific functional study showing normal RUNX1 function was identified, so BS3 cannot be applied.	cspec oncokb
BS4	Not assessed	No convincing non-segregation data were identified for this variant.	cspec clinvar
BP1	N/A	BP1 is not applicable in the RUNX1 VCEP framework.	cspec
BP2	Not assessed	No evidence was identified that this variant is in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 cannot be applied.	cspec clinvar
BP3	N/A	BP3 is not applicable in the RUNX1 VCEP framework.	cspec
BP4	Not met	Available computational evidence does not meet the RUNX1 BP4 rule. Although SpliceAI is 0.01 and is below the benign splice cutoff of 0.20, REVEL is 0.702 and is not below the BP4 missense cutoff of 0.50.	cspec revel spliceai bayesdel
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	N/A	BP6 is not used in this framework.	cspec
BP7	N/A	This variant is missense rather than synonymous or intronic, so BP7 does not apply.	cspec spliceai

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