RUNX1c.617dupPathogenic

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Variant interpretation report

RUNX1 c.617dup, p.(His206GlnfsTer7)

NM_001754.4:c.617dup NP_001745.2:p.(His206GlnfsTer7) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RUNX1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen RUNX1 VCEP v3.1.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (supporting): This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_supporting threshold of 0.00005.
PM5 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen RUNX1 VCEP v3.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

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.

PM2Supporting

PM2 · supporting

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

PM5Supporting

PM5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

RUNX1 MM-VCEP/CSPEC point-based Tavtigian framework v3.1.0: PVS1_VeryStrong (8) + PM2_Supporting (1) + PM5_Supporting (1) = 10 points, which meets the Pathogenic threshold (>=10).

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen RUNX1 VCEP v3.1.0, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 3 not met · 7 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 3

PVS1 Very strongThis 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PVS1 decision tree

Evidence considered

Frameshift consequence p.(His206GlnfsTer7)
RUNX1 loss of function established as disease mechanism
Variant-level PVS1 scaffold suggests default PVS1

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_supporting threshold of 0.00005. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PM2_Supporting

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1
PM2_supporting threshold <=0.00005

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 SupportingThe 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PM5_Supporting for nonsense/frameshift variants downstream of c.98

Evidence considered

Variant is downstream of c.98
SpliceAI max delta score 0.02
PM1 not met
RUNX1 MM-VCEP allows PM5_Supporting for downstream nonsense/frameshift variants

Sources

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

Not met · 3 · evaluated, threshold not reached

PM1 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PM1

Evidence considered

Protein change p.(His206GlnfsTer7)
RUNX1 PM1 region limited to residues 89-204

Sources

cspec ↗PMID:15386419 ↗PMID:15864279 ↗PMID:17394134 ↗

BA1 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP BA1

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1
BA1 threshold >=0.0015 with >=5 alleles

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP BS1

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1
BS1 threshold 0.00015-0.0015 with >=5 alleles

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 7 · no assessment recorded

PS2 No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 cannot be assessed. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PS2 requires confirmed de novo occurrence(s)

Evidence considered

No confirmed de novo evidence identified

Still missing

Confirmed de novo data in a patient with RUNX1-related phenotype

PS4 No proband-level evidence meeting the RUNX1 PS4 thresholds was identified, so PS4 cannot be assessed. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PS4 requires 1 or more qualifying probands

Evidence considered

No ClinVar submission identified for this variant
No qualifying proband count identified

Still missing

Proband-level observations in patients meeting RUNX1 phenotypic criteria

Sources

clinvar ↗

PM6 No assumed de novo occurrences were identified, so PM6 cannot be assessed. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PM6 requires assumed de novo occurrence(s)

Evidence considered

No assumed de novo evidence identified

Still missing

Assumed de novo occurrence data in patients with RUNX1-related phenotype

PP1 No segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PP1 requires 3 or more informative meioses

Evidence considered

No informative segregation evidence identified

Still missing

Informative family segregation data

BS3 Available evidence does not include qualifying variant-specific studies showing normal RUNX1 function, so BS3 cannot be applied. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP BS3 requires normal transactivation with supporting secondary data or normal transactivation alone for BS3_Supporting

Evidence considered

No qualifying normal-function assay identified for this variant

Still missing

Variant-specific functional studies showing normal transactivation
Secondary assay showing normal function

Sources

cspec ↗PMID:15386419 ↗PMID:15864279 ↗PMID:17394134 ↗

BS4 No non-segregation data were identified in informative meioses, so BS4 cannot be assessed. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP BS4 requires at least 2 informative meioses

Evidence considered

No informative non-segregation evidence identified

Still missing

Segregation data showing lack of co-segregation in 2 or more informative meioses

BP2 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. Details ▾Hide ▴

Rule

Original ACMG/AMP BP2 as adopted by RUNX1 MM-VCEP

Evidence considered

No cis/trans observation identified

Still missing

Phase data with a pathogenic variant

Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

Rule

RUNX1 MM-VCEP PS1

Evidence considered

Variant class is frameshift