Classification rationale

PM1PM2 VUS

RUNX1 c.590G>A

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

PM1 + PM2 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 oncokb ↗cspec ↗

4 cspec ↗revelspliceai ↗bayesdelvcep_myeloid_malignancy_vcep_runx1_pilot_results

Gene diagram · NM_001001890.2 · variants mapped to exon structure

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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

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)

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.702. BayesDel score = 0.137586.

SpliceAI ↗

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

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 14 PMIDs not cited in assessment

22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. CLINVAR

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. 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

20963938 ↗ PMID:20963938 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