Variant: NM_001754.5(RUNX1):c.812G>A (p.Arg271Lys)

Version: 1.0
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CA10014290

699735 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 3838deae-bde1-4eb8-8c28-ff7714f3e455

Approved on: 2024-06-24

Published on: 2024-06-24

HGVS expressions

NM_001754.5:c.812G>A
NM_001754.5(RUNX1):c.812G>A (p.Arg271Lys)
NC_000021.9:g.34799456C>T
CM000683.2:g.34799456C>T
NC_000021.8:g.36171753C>T
CM000683.1:g.36171753C>T
NC_000021.7:g.35093623C>T
NG_011402.2:g.1190256G>A
ENST00000675419.1:c.812G>A
ENST00000300305.7:c.812G>A
ENST00000344691.8:c.731G>A
ENST00000399240.5:c.539G>A
ENST00000437180.5:c.812G>A
ENST00000482318.5:c.*402G>A
NM_001001890.2:c.731G>A
NM_001754.4:c.812G>A
NM_001001890.3:c.731G>A

Benign

• Met criteria codes: BA1 BP4

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5 BP7 PS4 PS2 PS3 PS1 PVS1 PP1 PP4 PP3 PP2 PM6 PM2 PM1 PM5 PM3 PM4

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

This missense variant has been published in Taiwanese patients with CEBPA double-mutated, cytogenetically normal-AML (PMID: 29773598), pediatric T-ALL (PMID: 30280491), and ovarian cancer (PMID: 31761620), although germline origin was unknown for these cases. However, the variant has an MAF of 0.1854% (37/19952 alleles) in the East Asian subpopulation of the gnomAD cohort, which is ≥ 0.0015 (0.15%) (BA1). It also has a REVEL score <0.50 (0.326) and SpliceAI does not predict (Δ scores ≤ 0.20) a significant impact on the canonical splice sites or the creation of putative cryptic splice sites (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4.

Met criteria codes

• BA1: gnomAD (v2): ALL: 0.01308% (37/282814) - EAS: 0.1854% (37/19952) gnomAD (v3): ALL: 0.003287% (5/152106) - EAS: 0.09634% (5/5190)
• BP4: REVEL score = 0.326, which is less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).

Not Met criteria codes

• BS2: Not applicable
• BS4: Family studies were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• BS3: Functional studies were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• BS1: gnomAD (v2): ALL: 0.01308% (37/282814) - EAS: 0.1854% (37/19952) gnomAD (v3): ALL: 0.003287% (5/152106) - EAS: 0.09634% (5/5190)
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: Not applicable
• BP1: Not applicable
• BP5: Not applicable
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The variant has been published in patients from Taiwan: CEBPAdm-mutated CN-AML of a 41yo female (PMID: 29773598), a pediatric T-ALL (PMID: 30280491), and an ovarian tumor at VAF=29% (PMID: 31761620). However, germline origin is unknown for these cases.
• PS2: Germline confirmed/de novo cases were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• PS3: Functional studies were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: Family studies were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• PP4: Not applicable
• PP3: REVEL score = 0.326, which is not higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
• PP2: Not applicable
• PM6: Germline confirmed/de novo cases were not found in the literature (LOVD, HGMD, ClinVar, COSMIC, Google/Google Scholar, Mastermind).
• PM2: gnomAD (v2): ALL: 0.01308% (37/282814) - EAS: 0.1854% (37/19952) gnomAD (v3): ALL: 0.003287% (5/152106) - EAS: 0.09634% (5/5190)
• PM1: Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
• PM5: R271/R244 variants have not been reported in COSMIC or Mastermind.
• PM3: Not applicable
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline