Variant: NM_001754.5(RUNX1):c.281G>C (p.Ser94Thr)

Version: 1.0
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CA410203693

3068220 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 2e03431d-79bf-461e-ba49-709ca7880255

Approved on: 2025-01-15

Published on: 2025-01-15

HGVS expressions

NM_001754.5:c.281G>C
NM_001754.5(RUNX1):c.281G>C (p.Ser94Thr)
NC_000021.9:g.34886913C>G
CM000683.2:g.34886913C>G
NC_000021.8:g.36259210C>G
CM000683.1:g.36259210C>G
NC_000021.7:g.35181080C>G
NG_011402.2:g.1102799G>C
ENST00000675419.1:c.281G>C
ENST00000300305.7:c.281G>C
ENST00000344691.8:c.200G>C
ENST00000358356.9:c.200G>C
ENST00000399237.6:c.245G>C
ENST00000399240.5:c.200G>C
ENST00000437180.5:c.281G>C
ENST00000455571.5:c.242G>C
ENST00000482318.5:c.59-6200G>C
NM_001001890.2:c.200G>C
NM_001122607.1:c.200G>C
NM_001754.4:c.281G>C
NM_001001890.3:c.200G>C
NM_001122607.2:c.200G>C

Uncertain Significance

• Met criteria codes: PM1_Supporting PP3 PM2_Supporting

• Not Met criteria codes: PS2 PS4 PS3 PS1 PP1 PP4 PP2 PM6 PM5 PM3 PM4 BA1 PVS1 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1

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.281G>C (p.Ser94Thr) is a missense variant with a REVEL score ≥ 0.88 (0.931) (PP3). This variant is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported as likely pathogenic by clinical testing by the Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center (ClinVar ID 3068220), however, PS1 was not applied because it was not curated using the MM-VCEP rules for RUNX1. 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: PP3, PM1_supporting, PM2_Supporting.

Met criteria codes

• PM1_Supporting: This variant affects one of the other residues (AA 89-204) within the RHD, specifically residue 94 (PM1_Supporting).
• PP3: This missense variant has a REVEL score ≥ 0.88 (0.931) (PP3).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

Not Met criteria codes

• PS2: De novo data for this variant has not been reported in literature.
• PS4: The prevalence of the variant in affected individuals has not been reported to be significantly increased compared with the prevalence in controls.
• PS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• PS1: This variant c.281G>C (p.Ser94Thr) has been reported as likely pathogenic by clinical testing by the Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center (ClinVar ID 3068220), however, PS1 was not applied because it was not curated using the MM-VCEP rules for RUNX1.
• PP1: Segregation data for this variant has not been reported in literature.
• PP4: This rule is not applicable for MM-VCEP
• PP2: This rule is not applicable for MM-VCEP
• PM6: De novo data for this variant has not been reported in literature.
• PM5: There has not yet been a different missense change determined to be pathogenic at this amino acid residue.
• PM3: This rule is not applicable for MM-VCEP
• PM4: This variant is not an in-frame deletion/insertion.
• BA1: This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
• PVS1: This variant is not a null variant.
• BS4: Segregation data for this variant has not been reported in literature.
• BS3: In vitro or in vivo functional data has not been reported for this variant in the literature.
• BS1: This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
• BS2: This rule is not applicable for MM-VCEP
• BP7: This variant is not a synonymous or intronic variant.
• BP5: 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.
• 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