Variant: NM_001754.4(RUNX1):c.167T>C (p.Leu56Ser)

CA10014578

239045 (ClinVar)

Gene: RUNX1

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

Inheritance Mode: Autosomal dominant inheritance

UUID: 36a19c90-310a-4c8f-ad1d-8f186170daaa

HGVS expressions

NM_001754.4:c.167T>C
NM_001754.4(RUNX1):c.167T>C (p.Leu56Ser)
NC_000021.9:g.34887027A>G
CM000683.2:g.34887027A>G
NC_000021.8:g.36259324A>G
CM000683.1:g.36259324A>G
NC_000021.7:g.35181194A>G
NG_011402.2:g.1102685T>C
NM_001001890.2:c.86T>C
NM_001122607.1:c.86T>C
ENST00000300305.7:c.167T>C
ENST00000344691.8:c.86T>C
ENST00000358356.9:c.86T>C
ENST00000399237.6:c.131T>C
ENST00000399240.5:c.86T>C
ENST00000437180.5:c.167T>C
ENST00000455571.5:c.128T>C
ENST00000482318.5:c.59-6314T>C

Benign

• Met criteria codes: BA1 BS3 BP2

• Not Met criteria codes: PM2 PM6 PM5 PM4 PM1 PVS1 BS1 BS4 BP7 BP4 PS1 PS3 PS4 PP3 PP1

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID: 23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. 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, BS3, BP2.

Met criteria codes

• BA1: ExAC Allele Frequency of South Asian Subpopulation: 0.03259 (518 out of 15894 Alleles) > 0.0015
• BS3: Transactivation assays demonstrate normal transactivation (80-114% of WT). Secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization.
• BP2: This variant is detected in homozygous state (56) in gnomAD population database (BP2).

Not Met criteria codes

• PM2: 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
• PM1: 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
• BS1: 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: REVEL: 0.307
• 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
• PS4: Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1.
• PP3: REVEL: 0.307
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-07-26

Published on: 2019-08-02