Variant: NM_001754.5(RUNX1):c.367G>C (p.Asp123His)

CA10014524

429813 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 7e5378c7-f9d9-470d-9323-32fe9a5a69f7

Approved on: 2025-02-24

Published on: 2025-02-24

HGVS expressions

NM_001754.5:c.367G>C
NM_001754.5(RUNX1):c.367G>C (p.Asp123His)
NC_000021.9:g.34880698C>G
CM000683.2:g.34880698C>G
NC_000021.8:g.36252995C>G
CM000683.1:g.36252995C>G
NC_000021.7:g.35174865C>G
NG_011402.2:g.1109014G>C
ENST00000675419.1:c.367G>C
ENST00000300305.7:c.367G>C
ENST00000344691.8:c.286G>C
ENST00000358356.9:c.286G>C
ENST00000399237.6:c.331G>C
ENST00000399240.5:c.286G>C
ENST00000437180.5:c.367G>C
ENST00000455571.5:c.328G>C
ENST00000482318.5:c.74G>C
NM_001001890.2:c.286G>C
NM_001122607.1:c.286G>C
NM_001754.4:c.367G>C
NM_001001890.3:c.286G>C
NM_001122607.2:c.286G>C

Uncertain Significance

• Met criteria codes: BS3_Supporting PM1_Supporting PP1 PP3 PS4_Supporting

• Not Met criteria codes: BA1 BS2 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1 PS2 PS3 PS1 PP4 PP2 PM6 PM2 PM3 PM4 PM5

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

The NM_001754.5(RUNX1):c.367G>C (p.Asp123His) is a missense variant. Transactivation assays demonstrating normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 35026845). This variant was found to co-segregate with disease in multiple affected family members, with three or four (4) meioses observed in one family (PP1; PMID: 18723428). This missense variant has a REVEL score ≥ 0.88 (0.943) (PP3). This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting). This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 18723428, 35026845). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, PP1, PP3, PM1_supporting, PS4_supporting.

Met criteria codes

• BS3_Supporting: Transactivation assays demonstrating normal transactivation (80-115% of wt) (BS3_Supporting; PMID: 35026845).
• PM1_Supporting: This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).
• PP1: This variant was found to co-segregate with disease in multiple affected family members, with three or four (4) meioses observed in one family (PP1; PMID: 18723428).
• PP3: This missense variant has a REVEL score ≥ 0.88 (0.943) (PP3).
• PS4_Supporting: This variant has been reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 18723428, 35026845).

Not Met criteria codes

• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• BS2: This rule is not applicable for MM-VCEP
• BS4: Segregation was not found to be absent in two or more informative meiosis.
• 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 missense variant does not have a REVEL score < 0.50.
• BP1: This rule is not applicable for MM-VCEP
• BP5: This rule is not applicable for MM-VCEP
• BP7: This variant is not a synonymous or intronic variant.
• PVS1: This variant is not a null variant.
• PS2: This variant does not have a proven de novo occurrence in the literature.
• PS3: This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.
• PS1: There has not yet been a different missense change determined to be pathogenic at this amino acid residue.
• PP4: This rule is not applicable for MM-VCEP
• PP2: This rule is not applicable for MM-VCEP
• PM6: This variant does not have two or more assumed de novo occurrences in the literature.
• PM2: This variant is present in at least one population database.
• PM3: This rule is not applicable for MM-VCEP
• PM4: This variant is not an in-frame deletion/insertion.
• PM5: There has not yet been a different missense change determined to be pathogenic at this amino acid residue.