Variant classification summary

NM_001001890.2:c.1036T>G

RUNX1 · NP_001001890.1:p.(Ser346Ala) · NM_001001890.2

GRCh37: chr21:36164758 A>C · GRCh38: chr21:34792461 A>C

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.(Ser346Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The RUNX1 NM_001001890.2:c.1036T>G (p.(Ser346Ala)) 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 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2_Supporting under the RUNX1 threshold of <=0.00005.

3

Computational evidence argues against a damaging effect because REVEL is 0.262, below the RUNX1 PP3 threshold and within the BP4 range, SpliceAI shows no predicted splice impact with a max delta score of 0.00, and BayesDel is -0.17459.

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
PVS1	N/A	This missense variant does not create a nonsense, frameshift, or canonical +/-1,2 splice-site change, and available splice prediction does not indicate an RNA effect that would support a loss-of-function mechanism for PVS1.	pvs1_gene_context pvs1_variant_assessment cspec 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.	clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results cspec
PS2	Not met	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.	clinvar cspec
PS3	Not assessed	No variant-specific functional study demonstrating abnormal RUNX1 function was identified, so PS3 could not be evaluated from the available evidence.	oncokb cspec
PS4	Not met	No affected proband count or enrichment data were identified for this variant, so case-level overrepresentation has not been established.	clinvar gnomad_v2 gnomad_v4 cspec
PM1	Not met	This missense change affects Ser346, which is outside the RUNX1 Runt homology domain residues used by the RUNX1 specification for PM1, and no hotspot evidence supports this site as a critical region.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_Supporting threshold of <=0.00005.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the RUNX1 specification for this dominant disorder context.	cspec
PM4	N/A	PM4 is reserved for in-frame insertions/deletions affecting specified RUNX1 residues or for stop-loss variants, and this variant is a missense substitution.	cspec
PM5	Not met	No evidence was identified that a different pathogenic or likely pathogenic missense variant has been established at this same residue, so PM5 is not supported.	clinvar vcep_myeloid_malignancy_vcep_runx1_pilot_results cspec spliceai
PM6	Not met	No assumed de novo occurrences without full parental confirmation were identified for this variant.	clinvar cspec
PP1	Not met	No segregation data were identified for this variant, so cosegregation with RUNX1-related disease has not been established.	clinvar cspec
PP2	N/A	PP2 is not applicable in the RUNX1 specification.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect under the RUNX1 PP3 rule because REVEL is 0.262, below the >=0.88 threshold, and SpliceAI is 0.00, below the >=0.38 threshold.	revel spliceai cspec
PP4	N/A	PP4 is not applicable in the RUNX1 specification because the associated phenotype is not sufficiently specific for this criterion.	cspec
PP5	N/A	PP5 is not used in the RUNX1 specification.	cspec
BA1	Not met	This variant is absent from population databases and does not meet the RUNX1 BA1 threshold of >=0.0015 in a general population dataset.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from population databases and does not meet the RUNX1 BS1 range of 0.00015 to 0.0015.	gnomad_v2 gnomad_v4 cspec
BS2	N/A	BS2 is not applicable in the RUNX1 specification.	cspec
BS3	Not assessed	No variant-specific functional study showing normal RUNX1 activity was identified, so BS3 could not be evaluated from the available evidence.	oncokb cspec
BS4	Not met	No lack-of-segregation data were identified for this variant, so BS4 is not supported.	clinvar cspec
BP1	N/A	BP1 is not applicable in the RUNX1 specification.	cspec
BP2	Not met	No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant.	clinvar cspec
BP3	N/A	BP3 is not applicable in the RUNX1 specification.	cspec
BP4	Met	Computational evidence supports a benign interpretation because the REVEL score is 0.262, below the RUNX1 BP4 threshold of <0.50, and the SpliceAI max delta score is 0.00, within the <=0.20 threshold for no predicted splice impact. The BayesDel score of -0.17459 is also consistent with low predicted deleteriousness.	revel spliceai bayesdel cspec
BP5	N/A	BP5 is not applicable in the RUNX1 specification.	cspec
BP6	N/A	BP6 is not applicable in the RUNX1 specification.	cspec
BP7	N/A	BP7 is limited to qualifying synonymous or intronic variants, and this variant is missense.	cspec

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