Variant: NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp)

CA410202533

956982 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 19a477bd-cd94-44af-8ed4-557ecb1187c9

Approved on: 2024-07-17

Published on: 2024-07-17

HGVS expressions

NM_001754.5:c.475A>G
NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp)
NC_000021.9:g.34880590T>C
CM000683.2:g.34880590T>C
NC_000021.8:g.36252887T>C
CM000683.1:g.36252887T>C
NC_000021.7:g.35174757T>C
NG_011402.2:g.1109122A>G
ENST00000675419.1:c.475A>G
ENST00000300305.7:c.475A>G
ENST00000344691.8:c.394A>G
ENST00000358356.9:c.394A>G
ENST00000399237.6:c.439A>G
ENST00000399240.5:c.394A>G
ENST00000437180.5:c.475A>G
ENST00000482318.5:c.*65A>G
NM_001001890.2:c.394A>G
NM_001122607.1:c.394A>G
NM_001754.4:c.475A>G
NM_001001890.3:c.394A>G
NM_001122607.2:c.394A>G

Uncertain Significance

• Met criteria codes: PP3 BS3_Supporting PM1_Supporting PM2_Supporting

• Not Met criteria codes: PVS1 PS2 PS4 PS3 PS1 PP1 PP4 PP2 PM6 PM5 PM3 PM4 BA1 BS2 BS4 BS1 BP7 BP5 BP2 BP4 BP1 BP3

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

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.475A>G (p.Asn159Asp) is a missense variant affecting one of the residues within the runt homology domain (AA 89-204) (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.88 (0.956) (PP3). Transactivation assays demonstrate normal transactivation at 80.43% (80-115% of wt), suggesting functional similarity to the wild type (BS3_Supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_supporting, PM2_supporting, BS3_supporting, PP3.

Met criteria codes

• PP3: This missense variant has a REVEL score >0.88 (0.956) (PP3).
• BS3_Supporting: Transactivation assays demonstrating normal transactivation of 80.43% (80-115% of wt) (BS3_Supporting; PMID: 34166225).
• PM1_Supporting: This variant affects one of the other residues (AA 89-204) within the RHD (PM1_supporting).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: This rule is not applicable for MM-VCEP
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: This rule is not applicable for MM-VCEP
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• BP3: This rule is not applicable for MM-VCEP