Variant: NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)

CA248628

14471 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 1023c045-33cc-4c4b-9297-ea4832be8def

Approved on: 2024-06-24

Published on: 2024-06-24

HGVS expressions

NM_001754.5:c.467C>A
NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)
NC_000021.9:g.34880598G>T
CM000683.2:g.34880598G>T
NC_000021.8:g.36252895G>T
CM000683.1:g.36252895G>T
NC_000021.7:g.35174765G>T
NG_011402.2:g.1109114C>A
ENST00000675419.1:c.467C>A
ENST00000300305.7:c.467C>A
ENST00000344691.8:c.386C>A
ENST00000358356.9:c.386C>A
ENST00000399237.6:c.431C>A
ENST00000399240.5:c.386C>A
ENST00000437180.5:c.467C>A
ENST00000482318.5:c.*57C>A
NM_001001890.2:c.386C>A
NM_001122607.1:c.386C>A
NM_001754.4:c.467C>A
NM_001001890.3:c.386C>A
NM_001122607.2:c.386C>A

Likely Pathogenic

• Met criteria codes: PP3 PM2_Supporting PM1_Supporting PS4_Supporting PP1_Strong

• Not Met criteria codes: PS2 PS3 PS1 BA1 PP4 PP2 PM3 PM4 PM5 PM6 BS4 BS1 BS3 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PVS1

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_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). 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: PP1_Strong, PM2_supporting, PP3, PM1_Supporting, PS4_Supporting.

Met criteria codes

• PP3: This missense variant has a REVEL score ≥ 0.88 (0.906) (PP3).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
• PM1_Supporting: This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).
• PS4_Supporting: 1 affected proband in a family with FPD/AML (PMID: 19357396, PMID: 27112265).
• PP1_Strong: 8 affected individuals in one pedigree with 7 meioses.

Not Met criteria codes

• PS2: De novo data for this variant has not been reported in literature.
• PS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• 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.
• PP4: This rule is not applicable for MM-VCEP.
• PP2: This rule is not applicable for MM-VCEP.
• 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.
• PM6: De novo data for this variant has not been reported in literature.
• 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.
• BS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• BS2: 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.
• 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.
• PVS1: This variant is not a null variant.