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.1 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-05.2 No reviewed variant-specific functional evidence demonstrating either abnormal or normal RUNX1 function was identified, so the current evidence does not support PS3 or BS3.3 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 BP4.4
Final classification
VUS
PM1PM2
RUNX1
c.590G>A
p.Arg197Gln
This variant
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM1 supporting (+1) + PM2 supporting (+1) = 2 points, which maps to VUS.
Classification rationale
PM1PM2
VUS
RUNX1 c.590G>A
PM1 + PM2
→
VUS
4
cspec ↗revelspliceai ↗bayesdelvcep_myeloid_malignancy_vcep_runx1_pilot_results
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001001890.2 · variants mapped to exon structure
RUNX1
NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM1
supporting
Pathogenic
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.
Protein consequence p.(Arg197Gln)RUNX1 VCEP PM1 rule for residues 89-204pilot VCEP precedent showing PM1 use within this domain.
PM2
supporting
Pathogenic
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.
gnomAD v4.1 grpmax FAF 6.8e-07 and total AF 2.48e-06gnomAD v2.1 total AF 3.98e-06RUNX1 PM2_Supporting threshold <=0.00005.
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PVS1
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.
PS1
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.
PS2
No confirmed de novo occurrence with maternity and paternity established was identified for this variant.
PS3
No validated variant-specific functional assay showing abnormal RUNX1 activity was identified, so PS3 cannot be applied from the current evidence.
PS4
This variant has been reported in ClinVar, but no verified count of unrelated probands meeting RUNX1 phenotypic criteria was identified to support PS4.
PM5
No different missense variant at the same residue was verified as pathogenic or likely pathogenic in the reviewed evidence, so PM5 is not met.
PM6
No assumed de novo occurrences without full parental confirmation were identified for this variant.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
PP3
Available computational evidence does not meet the RUNX1 PP3 threshold.
Benign
BA1
Population frequency is far below the RUNX1 BA1 threshold.
BS1
Population frequency does not reach the RUNX1 BS1 range.
BS3
No validated variant-specific functional study showing normal RUNX1 function was identified, so BS3 cannot be applied.
BS4
No convincing non-segregation data were identified for this variant.
BP2
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.
BP4
Available computational evidence does not meet the RUNX1 BP4 rule.
N/A · 11
PM3 · PM4 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.48193e-06; MAF= 0.00025%, 4/1611650 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23264e-05; MAF= 0.00223%, 1/44790 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98492e-06; MAF= 0.00040%, 1/250946 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81368e-06; MAF= 0.00088%, 1/113460 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,611,650
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
East Asian 1 / 44,790 |
0.0022% |
European (non-Finnish) 3 / 1,179,746 |
0.00025% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 250,946
0 hom
0 hom
European (non-Finnish) 1 / 113,460 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 580214)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.702. BayesDel score = 0.137586.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 14 PMIDs not cited in assessment
22138009 ↗
NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.
CLINVAR
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23169492 ↗
The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
23881473 ↗
Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
CLINVAR
24022298 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR