Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.5(RUNX1):c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142fs)

CA2580098645

2029556 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1004a07f-fee6-417b-9cc4-69e0df4ad540

Approved on: 2024-08-28

Published on: 2024-08-28

HGVS expressions

NM_001754.5:c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001754.5(RUNX1):c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142fs)

NC_000021.9:g.34880642_34880643insCTTTTATTCCGATTCCCCTTGTCCGAAGGTAT

CM000683.2:g.34880642_34880643insCTTTTATTCCGATTCCCCTTGTCCGAAGGTAT

NC_000021.8:g.36252939_36252940insCTTTTATTCCGATTCCCCTTGTCCGAAGGTAT

CM000683.1:g.36252939_36252940insCTTTTATTCCGATTCCCCTTGTCCGAAGGTAT

NC_000021.7:g.35174809_35174810insCTTTTATTCCGATTCCCCTTGTCCGAAGGTAT

NG_011402.2:g.1109069_1109070insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000675419.1:c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000300305.7:c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000344691.8:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000358356.9:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000399237.6:c.386_387insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000399240.5:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000437180.5:c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000455571.5:c.383_384insATACCTTCGGACAAGGGGAATCGGAATAAAAG

ENST00000482318.5:c.*12_*13insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001001890.2:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001122607.1:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001754.4:c.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001001890.3:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

NM_001122607.2:c.341_342insATACCTTCGGACAAGGGGAATCGGAATAAAAG

Pathogenic

PM5_Supporting PM2_Supporting PS4_Supporting PVS1

PS3 PS2 PS1 BA1 PP1 PP4 PP3 PP2 PM1 PM3 PM4 PM6 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP7 BP5

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.422_423insATACCTTCGGACAAGGGGAATCGGAATAAAAG (p.Ala142TyrfsTer14) is a frameshift variant which is predicted to undergo nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_supporting; PMID: 31709191). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_supporting.

PM5_Supporting

This variant is a nonsense/frameshift variants 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).

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 31709191). PMID: 28933735 - only reported somatic variants PMID: 31709191 - 1 de novo AML patient with the p.Ala142fs variant PMID: 37051756 - no commentary on if germline or somatic

PVS1

This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (frameshift (-) c.98-c.758 as per VCEP specifications) (PVS1).

PS3

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

PS2

There is one meeting at least one of the RUNX1-phenotypic criteria with proven de novo AML occurrence (without confirmation of maternity and paternity) (PS2; PMID: 31709191). Unclear about family history, so opted for PS4_Supporting instead.

PS1

There has not yet been a missense change determined to be pathogenic at this amino acid residue.

BA1

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

PP1

This variant was not found to co-segregate with disease in 3 or more affected family members in the literature.

PP4

This rule is not applicable for MM-VCEP.

PP3

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

PP2

This rule is not applicable for MM-VCEP.

PM1

This variant is not a missense variant.

PM3

This rule is not applicable for MM-VCEP.

PM4

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

PM6

This variant does not have two or more assumed de novo occurrences in the literature.

BS2

This rule is not applicable for MM-VCEP.

BS3

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

BS4

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

BS1

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

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.

BP3

This rule is not applicable for MM-VCEP.

BP4

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

BP1

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BP5

This rule is not applicable for MM-VCEP.

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