Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.5(RUNX1):c.967_968insATCAA (p.Thr323fs)

Curation Version - 1.0
Curation History
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3766477 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1f9b9ab0-9f7a-4828-aa9f-89a8512ce61c

Approved on: 2025-03-26

Published on: 2025-03-26

HGVS expressions

NM_001754.5:c.967_968insATCAA

NM_001754.5(RUNX1):c.967_968insATCAA (p.Thr323fs)

Likely Pathogenic

PVS1_Strong PM5_Supporting PM2_Supporting

BA1 PM1 PM3 PM4 PM6 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP7 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.967_968insATCAA (p.Thr323fs) is a frameshift variant which is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong). This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM5_supporting, PM2_supporting.

PVS1_Strong

This variant is not predicted to undergo NMD, and the truncated/altered region is critical for protein function (frameshift (-) c.759-c.1440 as per VCEP specifications) (PVS1_Strong).

PM5_Supporting

This variant is a frameshift variant that is downstream of c.98 (PM5_Supporting).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

PM1

This variant is not a missense variant.

PM3

This rule is not applicable for RUNX1.

PM4

This variant is not an in-frame deletion/insertion.

PM6

De novo data for this variant has not been reported in literature.

BS2

This rule is not applicable for RUNX1.

BS1

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

BS4

Segregation data for this variant has not been reported in literature.

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BP4

This is a not a missense, synonymous, or intronic variant.

BP3

This rule is not applicable for RUNX1.

BP1

This rule is not applicable for RUNX1.

BP2

This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP7

This variant is not a synonymous or intronic variant.

PS1

This variant is not a missense variant.

PS2

De novo data for this variant has not been reported in literature.

PS3

There is evidence of abnormal DNA binding, but no transactivation assay has been performed.

PS4

Proband data for this variant has not been reported in literature.

PP1

Segregation data for this variant has not been reported in literature.

PP2

This rule is not applicable for RUNX1.

PP3

This is a not a missense, synonymous, or intronic variant.

PP4

This rule is not applicable for RUNX1.

Curation History

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