Variant classification summary

NM_001001890.2:c.1094A>C

RUNX1 · NP_001001890.1:p.(Gln365Pro) · NM_001001890.2

GRCh37: chr21:36164700 T>G · GRCh38: chr21:34792403 T>G

Gene: RUNX1 Transcript: NM_001001890.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

RUNX1

Transcript

NM_001001890.2

Protein

NP_001001890.1:p.(Gln365Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 NM_001001890.2:c.1094A>C (p.Gln365Pro, p.Q365P) variant has been reported in ClinVar and is currently classified there as a variant of uncertain significance by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1565090 alleles observed in gnomAD v4.1, which supports very low population frequency for RUNX1 disease.

3

Computational evidence does not support a damaging effect, with REVEL 0.245, SpliceAI maximum delta score 0.00, and BayesDel -0.122289; these findings support BP4 and do not support PP3.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework yields a total score of 0, 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
PP4	N/A	RUNX1 VCEP guidance states that PP4 is not applicable because the RUNX1-related phenotype is not sufficiently specific to support this criterion.	cspec
PVS1	Not met	This is a missense variant, not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00. Available evidence does not support a loss-of-function mechanism for this specific change, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PP1	Not assessed	No segregation data were identified to show that this variant tracks with RUNX1-related disease in affected relatives, so PP1 cannot be assessed from the available evidence.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied.	cspec clinvar
BP2	Not assessed	No data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed.	cspec clinvar
PP5	N/A	RUNX1 VCEP guidance does not allow use of PP5.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is also absent from gnomAD v4.1, with 0/1565090 alleles observed overall and 0/73964 alleles in the highest observed subpopulation. The observed frequency is below the RUNX1 VCEP PM2_Supporting threshold of 0.00005, so PM2_Supporting is met.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing normal RUNX1 function for this specific variant was identified, so BS3 cannot be assessed.	cspec oncokb
PM4	N/A	PM4 in the RUNX1 specification applies to in-frame insertions or deletions and stop-loss variants. This is a missense substitution, so PM4 is not applicable.	cspec
BP4	Met	For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP BP4 threshold of 0.50, and SpliceAI shows a maximum delta score of 0.00, which is at or below the BP4 threshold of 0.20. BayesDel is also negative at -0.122289, which does not support a damaging effect. These computational results support BP4.	cspec revel spliceai bayesdel
BP3	N/A	RUNX1 VCEP guidance does not allow use of BP3.	cspec
PS1	Not assessed	No previously established pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed ClinVar summary or RUNX1 VCEP pilot materials, so PS1 cannot be applied from the available evidence.	cspec clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results
PM6	Not assessed	No assumed de novo occurrences without parentage confirmation were identified, so PM6 cannot be assessed.	cspec clinvar
PM5	Not assessed	No previously established pathogenic or likely pathogenic missense variant at this amino acid residue was identified in the reviewed evidence, so PM5 cannot be applied from the available materials.	cspec clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results spliceai
BP6	N/A	RUNX1 VCEP guidance does not allow use of BP6.	cspec
BP7	N/A	BP7 is limited to synonymous and certain intronic variants. This is a missense variant, so BP7 is not applicable.	cspec
BP5	N/A	RUNX1 VCEP guidance does not allow use of BP5.	cspec
PS4	Not assessed	This variant is reported in ClinVar, but no proband-level evidence was identified showing 1 or more affected individuals meeting RUNX1 VCEP phenotypic criteria. Available evidence is insufficient to assess PS4.	cspec clinvar
BS4	Not assessed	No non-segregation data with at least 2 informative meioses were identified, so BS4 cannot be assessed.	cspec clinvar
BS2	N/A	RUNX1 VCEP guidance does not allow use of BS2.	cspec
PM1	Not met	The RUNX1 VCEP PM1 region is restricted to residues 89-204 within the Runt homology domain, with stronger weighting for 13 specific residues. This variant affects p.Gln365Pro, which lies outside that region, so PM1 is not met.	cspec
PP3	Not met	For this missense variant, REVEL is 0.245, which is below the RUNX1 VCEP PP3 threshold of 0.88, and SpliceAI shows a maximum delta score of 0.00, which is below the PP3 threshold of 0.38. These computational results do not support PP3.	cspec revel spliceai
PP2	N/A	RUNX1 VCEP guidance does not allow use of PP2.	cspec
BA1	Not met	This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1. The observed frequency is below the RUNX1 VCEP BA1 threshold of 0.0015, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
PS3	Not assessed	No well-established functional study showing abnormal RUNX1 function for this specific variant was identified, so PS3 cannot be assessed.	cspec oncokb
BP1	N/A	RUNX1 VCEP guidance does not allow use of BP1.	cspec
PM3	N/A	RUNX1 VCEP guidance does not allow use of PM3.	cspec
BS1	Not met	This variant is absent from gnomAD, with 0/1565090 alleles observed in gnomAD v4.1. The observed frequency is below the RUNX1 VCEP BS1 range of 0.00015 to 0.0015, so BS1 is not met.	cspec gnomad_v2 gnomad_v4

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.