Variant classification summary

NM_001001890.2:c.619A>G

RUNX1 · NP_001001890.1:p.(Thr207Ala) · NM_001001890.2

GRCh37: chr21:36206812 T>C · GRCh38: chr21:34834515 T>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.(Thr207Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 NM_001001890.2:c.619A>G (p.(Thr207Ala)) variant has been reported in ClinVar and is currently classified there 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 is present at very low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07, which supports PM2 at supporting strength under the RUNX1 VCEP threshold of 0.00005.

3

Computational data do not support a splice effect, with SpliceAI max delta score 0.01, and the missense prediction is indeterminate under the RUNX1 VCEP computational rules because REVEL is 0.581, below the PP3 threshold of 0.88 and above the BP4 threshold of 0.50; BayesDel is 0.0617795.

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	Not met	This is a missense substitution, p.(Thr207Ala), and does not fall into the RUNX1 loss-of-function variant categories used for PVS1. Available splicing data also do not support a rescue of PVS1 through an abnormal splice effect, with SpliceAI max delta score 0.01.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	No evidence was identified that this variant causes the same amino acid change as a previously established pathogenic or likely pathogenic RUNX1 variant.	cspec vcep_myeloid_malignancy_vcep_runx1_pilot_results clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity testing was identified for this variant.	cspec clinvar
PS3	Not assessed	No published variant-specific functional study was identified showing altered RUNX1 transactivation or abnormal secondary assay results for this variant.	cspec oncokb
PS4	Not assessed	This variant is reported in ClinVar, but no proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment under the RUNX1 PS4 rules.	cspec clinvar
PM1	Not met	This missense variant affects Thr207, which is outside the RUNX1 VCEP PM1-defined residues 89-204 in the Runt homology domain, and available hotspot review did not identify a statistically significant hotspot at this residue.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07. This is below the RUNX1 PM2_Supporting threshold of 0.00005 with more than 2,000 alleles evaluated.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the RUNX1 VCEP framework.	cspec
PM4	N/A	This 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 evidence was identified for a different pathogenic or likely pathogenic missense change at this same amino acid residue, and SpliceAI does not suggest a splice effect that would alter the interpretation of a missense comparison.	cspec spliceai vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant in affected relatives.	cspec clinvar
PP2	N/A	PP2 is not applicable in the RUNX1 VCEP framework.	cspec
PP3	Not met	Computational evidence does not meet the RUNX1 PP3 threshold. REVEL is 0.581, which is below the PP3 threshold of 0.88, and SpliceAI max delta score is 0.01, which is below the PP3 splice threshold of 0.38.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is designated not applicable by the RUNX1 VCEP because the RUNX1-associated phenotype is not sufficiently specific for this criterion.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	Population frequency does not meet the RUNX1 BA1 threshold. The observed gnomAD v4.1 frequency is 2/1,612,820 alleles (0.00012%), which is far below the BA1 threshold of 0.15%.	cspec gnomad_v4
BS1	Not met	Population frequency does not meet the RUNX1 BS1 threshold. The observed gnomAD v4.1 frequency is 2/1,612,820 alleles (0.00012%), which is below the BS1 range of 0.015% to 0.15%.	cspec gnomad_v4
BS2	N/A	BS2 is not applicable in the RUNX1 VCEP framework.	cspec
BS3	Not assessed	No published variant-specific functional study was identified showing normal RUNX1 transactivation or normal secondary assay results for this variant.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.	cspec
BP1	N/A	BP1 is not applicable in the RUNX1 VCEP framework.	cspec
BP2	Not assessed	No evidence was identified that this variant occurs in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.	cspec
BP3	N/A	BP3 is not applicable in the RUNX1 VCEP framework.	cspec
BP4	Not met	Computational evidence does not meet the RUNX1 BP4 threshold. SpliceAI max delta score is 0.01 and is compatible with no splice effect, but REVEL is 0.581, which is above the BP4 threshold of 0.50. BayesDel is 0.0617795, but the RUNX1 VCEP BP4 rule for missense variants requires both REVEL <0.50 and SpliceAI <=0.20.	cspec spliceai revel bayesdel
BP5	N/A	BP5 is not applicable in the RUNX1 VCEP framework.	cspec
BP6	N/A	BP6 is not applicable in the RUNX1 VCEP framework.	cspec
BP7	N/A	BP7 is limited to synonymous and intronic variants in the RUNX1 VCEP framework and does not apply to this missense variant.	cspec

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