Variant: NM_001754.5(RUNX1):c.958C>T (p.Arg320Ter)

CA410149580

618862 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: eca0a471-83bb-4860-bfa2-b0943d4a59e6

HGVS expressions

NM_001754.5:c.958C>T
NM_001754.5(RUNX1):c.958C>T (p.Arg320Ter)
NC_000021.9:g.34799310G>A
CM000683.2:g.34799310G>A
NC_000021.8:g.36171607G>A
CM000683.1:g.36171607G>A
NC_000021.7:g.35093477G>A
NG_011402.2:g.1190402C>T
ENST00000675419.1:c.958C>T
ENST00000300305.7:c.958C>T
ENST00000344691.8:c.877C>T
ENST00000399240.5:c.685C>T
ENST00000437180.5:c.958C>T
ENST00000482318.5:c.*548C>T
NM_001001890.2:c.877C>T
NM_001754.4:c.958C>T
NM_001001890.3:c.877C>T

Pathogenic

• Met criteria codes: PVS1_Strong PM5_Supporting PM2_Supporting PP1_Strong PS4_Moderate

• Not Met criteria codes: PS2 PS1 PS3 PP4 PP3 PP2 PM3 PM1 PM4 PM6 BA1 BS2 BS3 BS4 BS1 BP5 BP7 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

The NM_001754.4:c.958C>T (p.Arg320Ter) variant is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 320 - 480) is critical to protein function (PVS1_Strong). This variant was found to co-segregate with disease in multiple affected family members, with more than seven (14) meioses observed across 2 families (PP1_Strong; from internal laboratory data). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; from internal laboratory data). 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: PVS1_Strong, PP1_Strong, PM2_supporting, PS4_Moderate, PM5_supporting.

Met criteria codes

• PVS1_Strong: The variant occurs after the c.916 cutoff and hence NMD is not predicted. But the truncated region of RUNX1 is critical to protein function.
• PM5_Supporting: This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).
• PM2_Supporting: This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
• PP1_Strong: A total of 14 (13 + 1) segregations observed across two families (from internal laboratory data) meets criteria for PP1_Strong
• PS4_Moderate: 2 probands from internal laboratory data meet RUNX-1 phenotypic criteria. 2 meeting abstracts (Patton et al, 2007 & Rossini et al, 2012) also report this mutation in the germline of patients with FPD/AML. However, there is insufficient information available for them to be included for PS4 proband counting.

Not Met criteria codes

• PS2: De novo data for this variant has not been reported in literature.
• PS1: This variant is not a missense, or synonymous variant.
• PS3: Arg320Ter did not show significant transactivation (<20% of WT). The evidence does not meet criteria for PS3_Moderate due to the lack of pathogenic controls in the transactivation experiments.
• PP4: This rule is not applicable for MM-VCEP.
• PP3: This variant does not have applicable in-silico data available.
• PP2: This rule is not applicable for MM-VCEP.
• PM3: This rule is not applicable for MM-VCEP.
• PM1: This variant is not a missense variant.
• PM4: This variant is not an in-frame deletion/insertion.
• PM6: 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.
• BS2: This rule is not applicable for MM-VCEP.
• 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.
• 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.
• 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 variant does not have applicable in-silico data available.
• BP1: This rule is not applicable for MM-VCEP.

Approved on: 2024-03-26

Published on: 2024-03-26