Variant: NM_001754.5(RUNX1):c.328A>G (p.Lys110Glu)

CA248613

14465 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 37efba9c-0430-4e4f-a3ce-fc8c501d717a

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.328A>G
NM_001754.5(RUNX1):c.328A>G (p.Lys110Glu)
NC_000021.9:g.34886866T>C
CM000683.2:g.34886866T>C
NC_000021.8:g.36259163T>C
CM000683.1:g.36259163T>C
NC_000021.7:g.35181033T>C
NG_011402.2:g.1102846A>G
ENST00000675419.1:c.328A>G
ENST00000300305.7:c.328A>G
ENST00000344691.8:c.247A>G
ENST00000358356.9:c.247A>G
ENST00000399237.6:c.292A>G
ENST00000399240.5:c.247A>G
ENST00000437180.5:c.328A>G
ENST00000455571.5:c.289A>G
ENST00000482318.5:c.59-6153A>G
NM_001001890.2:c.247A>G
NM_001122607.1:c.247A>G
NM_001754.4:c.328A>G
NM_001001890.3:c.247A>G
NM_001122607.2:c.247A>G

Pathogenic

• Met criteria codes: PM2_Supporting PP1_Strong PS3 PS4_Supporting PP3 PM1 PM5_Supporting

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

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

Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). 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: PS3, PP1_Strong, PM1, PM2_supporting, PP3, PS4_Supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
• PP1_Strong: In 1 pedigree, 7 meioses observed for LEUKEMIA. 12 meioses if also including "bleeding disorder and/or platelet defect".
• PS3: Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization.
• PS4_Supporting: 1 (compelling) pedigee identified in the literature.
• PP3: This missense variant has a REVEL score ≥ 0.88 (0.953) (PP3).
• PM1: Residue that affects DNA binding as a mutational hot spot.
• PM5_Supporting: This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting).

Not Met criteria codes

• BP5: This rule is not applicable for MM-VCEP.
• BP7: This variant is not a synonymous or intronic variant.
• BP4: This missense variant does not have a REVEL score < 0.50.
• BP3: This rule is not applicable for MM-VCEP.
• BP1: This rule is not applicable for MM-VCEP.
• 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.
• PVS1: This variant is not a null variant.
• PS1: There has not yet been a missense change resulting in the same change in protein which has been determined to be pathogenic at this amino acid residue.
• PS2: De novo data for this variant has not been reported in literature.
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• PP2: This rule is not applicable for MM-VCEP.
• PP4: 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.
• PM6: De novo data for this variant has not been reported in literature.
• BS2: This rule is not applicable for MM-VCEP.
• BS1: This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
• BS4: Segregation was not found to be absent in two or more informative meiosis.
• BS3: This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.