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.319C>T (p.Arg107Cys)

CA410203489

1338536 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 21a8e654-df9e-4889-bfdc-9ea5e5c0fde6

HGVS expressions

NM_001754.5:c.319C>T

NM_001754.5(RUNX1):c.319C>T (p.Arg107Cys)

NC_000021.9:g.34886875G>A

CM000683.2:g.34886875G>A

NC_000021.8:g.36259172G>A

CM000683.1:g.36259172G>A

NC_000021.7:g.35181042G>A

NG_011402.2:g.1102837C>T

ENST00000675419.1:c.319C>T

ENST00000300305.7:c.319C>T

ENST00000344691.8:c.238C>T

ENST00000358356.9:c.238C>T

ENST00000399237.6:c.283C>T

ENST00000399240.5:c.238C>T

ENST00000437180.5:c.319C>T

ENST00000455571.5:c.280C>T

ENST00000482318.5:c.59-6162C>T

NM_001001890.2:c.238C>T

NM_001122607.1:c.238C>T

NM_001754.4:c.319C>T

NM_001001890.3:c.238C>T

NM_001122607.2:c.238C>T

Likely Pathogenic

PM1 PM2_Supporting PS3_Moderate PP3

PS2 PS4 PS1 PM5 PM4 PM3 PM6 BA1 PVS1 BP3 BP2 BP4 BP1 BP7 BP5 BS2 BS4 BS3 BS1 PP1 PP4 PP2

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

This variant affects one of the hotspot residues (residue 107) established by the MM-VCEP for RUNX1 (PM1).The variant exhibits altered function in 2 secondary assays. https://www.embopress.org/doi/epdf/10.1038/sj.emboj.7601568?src=getftr NM001001890.3 c.238C>T p.R80C - Moderate to severe loss of DNA binding and >5 fold decrease in CBFB binding (PS3_moderate).REVEL score is ≥0.88 (0.923) and SpliceAI is ≤0.20 (0.00) (PP3). This variant is completely absent from population databases (gnomad v4.0) 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: PM1, PS3_moderate, PP3, PM2_supporting.

PM1

This variant affects one of the hotspot residues (residue 107) established by the MM-VCEP for RUNX1 (PM1).

PM2_Supporting

This variant is completely absent from population databases (gnomad v4.0) with at least 20x coverage for RUNX1 (PM2_supporting).

PS3_Moderate

The variant exhibits altered function in 2 secondary assays. https://www.embopress.org/doi/epdf/10.1038/sj.emboj.7601568?src=getftr NM001001890.3 c.238C>T p.R80C - Moderate to severe loss of DNA binding and >5 fold decrease in CBFB binding

PP3

REVEL score is ≥0.88 (0.923) and SpliceAI is ≤0.20 (0.00) (PP3)

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

Somatic hotspot - reviewed 41 pubs - none confirmed germline.

PS1

Not same Amino Acid change

PM5

Cannot be applied due to the application of PM1

PM4

Not a frameshift variant

PM3

This rule is not applicable for MM-VCEP

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PVS1

Not a null variant

BP3

This rule is not applicable for MM-VCEP

BP2

No homozygotes present in gnomAD v2.1.1. or v3.1.2

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP1

This rule is not applicable for MM-VCEP

BP7

Not a synonymous or intronic variant

BP5

This rule is not applicable for MM-VCEP

BS2

This rule is not applicable for MM-VCEP

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

This rule is not applicable for MM-VCEP

PP2

This rule is not applicable for MM-VCEP

Approved on: 2023-12-09

Published on: 2023-12-09

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