NM_001754.4:c.506G>T

CA410202469

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 35141b76-e7bf-4e0e-977a-0f8379520709

HGVS expressions

NM_001754.4:c.506G>T
NC_000021.9:g.34880559C>A
CM000683.2:g.34880559C>A
NC_000021.8:g.36252856C>A
CM000683.1:g.36252856C>A
NC_000021.7:g.35174726C>A
NG_011402.2:g.1109153G>T
NM_001001890.2:c.425G>T
NM_001122607.1:c.425G>T
ENST00000300305.7:c.506G>T
ENST00000344691.8:c.425G>T
ENST00000358356.9:c.425G>T
ENST00000399237.6:c.470G>T
ENST00000399240.5:c.425G>T
ENST00000437180.5:c.506G>T
ENST00000482318.5:c.*96G>T

Likely Pathogenic

• Met criteria codes: PS4_Supporting PP1 PP3 PM1 PM2

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

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.506G>T (p.Arg169Ile) variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in one family (PP1; from internal laboratory data). This missense variant has a REVEL score >0.75 (0.939) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; from internal laboratory data). 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: PM1, PM2, PP1, PP3, PS4_Supporting.

Met criteria codes

• PS4_Supporting: 1 proband meeting RUNX1-phenotypic criteria (from internal laboratory data).
• PP1: 4 meioses observed within one family (from internal laboratory data) meeting criteria for PP1
• PP3: Revel score of 0.939 (threshold: >0.75)
• PM1: Affects defined hotspot residue in RUNT domain for PM1
• PM2: Not in 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
• 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
• 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
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Not present in population databases
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: 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
• BP7: 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
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2020-01-14

Published on: 2020-01-14