NM_001754.4:c.617dupA

RUNX1 · NP_001745.2:p.(His206GlnfsTer7) · NM_001754.4

GRCh37: chr21:36206894 A>AT · GRCh38: chr21:34834597 A>AT

Gene: RUNX1 Transcript: NM_001754.4

Final call

Pathogenic

PVS1_VeryStrong PM2_Supporting PM5_Supporting

Variant details

Gene

RUNX1

Transcript

NM_001754.4

Protein

NP_001745.2:p.(His206GlnfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The RUNX1 c.617dup (p.His206GlnfsTer7; p.H206Qfs*7) variant has not been reported in ClinVar, and OncoKB lists p.H206Qfs*7 as Likely Oncogenic with a likely loss-of-function effect.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in the general population and is below the RUNX1 PM2_supporting threshold of 0.00005.

This variant is a truncating frameshift, and the RUNX1 MM-VCEP framework recognizes loss of function as an established disease mechanism for RUNX1; the available PVS1 assessment supports full-strength PVS1 for this variant.

SpliceAI predicts no significant splice effect, with a maximum delta score of 0.02, which is below the 0.20 threshold and is consistent with the RUNX1 PM5_supporting rule for downstream nonsense or frameshift variants.

Final determination: Under the RUNX1 MM-VCEP point-based framework, a total of 10 points from PVS1_VeryStrong, PM2_Supporting, and PM5_Supporting meets the Pathogenic threshold.

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	The RUNX1 MM-VCEP specification states that PP4 should not be used because the FPD/AML phenotype is not sufficiently specific for a single genetic etiology.	cspec
PVS1	Met	This variant is a frameshift predicted to result in p.(His206GlnfsTer7), and loss of function is an established disease mechanism for RUNX1 in the MM-VCEP framework. The available PVS1 assessment supports full-strength PVS1 for this truncating variant.	cspec pvs1_gene_context pvs1_variant_assessment
PP1	Not assessed	No segregation data were identified, so PP1 cannot be assessed.
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 cannot be assessed.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 cannot be assessed.
PP5	N/A	PP5 is not used by this VCEP.	cspec
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.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Available evidence does not include qualifying variant-specific studies showing normal RUNX1 function, so BS3 cannot be applied.	cspec PMID:15386419 PMID:15864279 PMID:17394134
PM4	N/A	PM4 in the RUNX1 specification applies to in-frame insertions or deletions and stop-loss variants. This variant is a frameshift, so PM4 is not applicable.	cspec
BP4	N/A	BP4 in the RUNX1 specification is used for missense, synonymous, and intronic variants. This frameshift variant is not eligible for BP4.	cspec
BP3	N/A	BP3 is not used by this VCEP.	cspec
PS1	N/A	PS1 is intended for the same amino acid change as a previously established pathogenic or likely pathogenic variant. This variant is a frameshift and does not fit that evidence model.	cspec
PM6	Not assessed	No assumed de novo occurrences were identified, so PM6 cannot be assessed.
PM5	Met	The RUNX1 MM-VCEP specification permits PM5_supporting for nonsense or frameshift variants downstream of c.98 when PM1 is not applied and splicing is not predicted to be affected. This variant is c.617dup, PM1 is not met, and SpliceAI predicts a maximum delta score of 0.02, which is below the 0.20 threshold.	cspec spliceai vcep_m_y_e_l_o_i_d___m_a_l_i_g_n_a_n_c_y___v_c_e_p___r_u_n_x_1___p_i_l_o_t___r_e_s_u_l_t_s
BP6	N/A	BP6 is not used by this VCEP.	cspec
BP7	N/A	BP7 applies to synonymous and intronic variants. This frameshift variant is not eligible for BP7.	cspec
BP5	N/A	BP5 is not used by this VCEP.	cspec
PS4	Not assessed	No proband-level evidence meeting the RUNX1 PS4 thresholds was identified, so PS4 cannot be assessed.	clinvar
BS4	Not assessed	No non-segregation data were identified in informative meioses, so BS4 cannot be assessed.
BS2	N/A	BS2 is not used by this VCEP.	cspec
PM1	Not met	This variant affects His206, which lies outside the RUNX1 residues eligible for PM1. The RUNX1 PM1 region is limited to residues 89-204, with a stronger subset at 13 specified residues, so PM1 is not met.	cspec
PP3	N/A	PP3 in the RUNX1 specification is used for missense, synonymous, and selected intronic variants, and not for canonical splice variants. This frameshift variant is not eligible for PP3.	cspec
PP2	N/A	PP2 is not used by this VCEP.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 BA1 threshold of 0.0015 in a continental population and does not meet the requirement for at least 5 observed alleles.	cspec gnomad_v2 gnomad_v4
PS3	N/A	The RUNX1 MM-VCEP specification states that PS3 is not applied when a variant already meets PVS1. This variant meets PVS1.	cspec pvs1_variant_assessment
BP1	N/A	BP1 is not used by this VCEP.	cspec
PM3	N/A	PM3 is not used by this VCEP.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 BS1 frequency range of 0.00015 to 0.0015 and does not meet the requirement for at least 5 observed alleles.	cspec gnomad_v2 gnomad_v4

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