Variant: NM_001754.4(RUNX1):c.467C>A (p.Ala156Glu)

CA248628

14471 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

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

HGVS expressions

NM_001754.4:c.467C>A
NM_001754.4(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
NM_001001890.2:c.386C>A
NM_001122607.1:c.386C>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

Likely Pathogenic

• Met criteria codes: PP1_Strong PM1_Supporting PS4_Supporting PP3 PM2

• Not Met criteria codes: PVS1 BA1 BS3 BS1 BS4 BP4 BP2 BP7 PS1 PS3 PM6 PM5 PM4

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

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). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). 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). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). 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, PP3, PM1_Supporting, PS4_Supporting.

Met criteria codes

• PP1_Strong: 8 affected individuals in one pedigree with 7 meioses.
• PM1_Supporting: Residue in RUNT domain (105-204aa).
• PS4_Supporting: 1 affected proband in a family with FPD/AML (PMID: 19357396, PMID: 27112265).
• PP3: REVEL: 0.906 >0.75
• PM2: The variant is absent from all population databases.

Not Met criteria codes

• PVS1: 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
• BS3: 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: 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
• PS1: 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
• 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
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-07-30

Published on: 2019-08-02