Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.952T>G (p.Ser318Ala)

CA10014261

415833 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 438020c8-369d-4532-9123-8f449f2ff97f
Approved on: 2021-01-11
Published on: 2021-01-11

HGVS expressions

NM_001754.4:c.952T>G
NM_001754.4(RUNX1):c.952T>G (p.Ser318Ala)
NM_001001890.2:c.871T>G
NM_001001890.3:c.871T>G
NM_001754.5:c.952T>G
ENST00000300305.7:c.952T>G
ENST00000344691.8:c.871T>G
ENST00000399240.5:c.679T>G
ENST00000437180.5:c.952T>G
ENST00000482318.5:c.*542T>G
NC_000021.9:g.34799316A>C
CM000683.2:g.34799316A>C
NC_000021.8:g.36171613A>C
CM000683.1:g.36171613A>C
NC_000021.7:g.35093483A>C
NG_011402.2:g.1190396T>G
More

Benign

Met criteria codes 2
BP4 BA1
Not Met criteria codes 16
BS1 BS3 BS4 PVS1 BP2 BP7 PS4 PS1 PS3 PP3 PP1 PM2 PM6 PM1 PM5 PM4

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
This missense variant is present in gnomAD (v2) at an allele frequency 0.6377% >0.15% with 226 out of 35438 alleles in Latino subpopulation (BA1). Additionally, this missense variant has a REVEL score <0.15 (0.093), and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4.
Met criteria codes
BP4
REVEL score=0.093, which is <0.15 threshold. SSF and MES at the canonical splice site show an increase or no more than a 10% score change and no putative cryptic splice sites are created.
BA1
ALL:0.08130% (230/282886 alleles) - AMR:0.6377% (226) - OTH:0.04153% (3) - SAS:0.003266% (1) (gnomAD v2) ALL:0.01256% (18/143302 alleles) - AMR:0.1245% (17) - AFR:0.002379% (1) (gnomAD v3)
Not Met criteria codes
BS1
ALL:0.08130% (230/282886 alleles) - AMR:0.6377% (226) - OTH:0.04153% (3) - SAS:0.003266% (1) (gnomAD v2) ALL:0.01256% (18/143302 alleles) - AMR:0.1245% (17) - AFR:0.002379% (1) (gnomAD v3)
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
PVS1
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
Not applicable
PS4
PS4 cannot be applied because the variant presents more than 1 time in gnomAD.
A proband with skeletal dysplasia and his father were heterozygous for S318A based on WES survey. However, this variant was considered to be irrelevant to the patient's phenotype (Supplementary Table 1) and the candidate gene was PKDCC. PubMed:30478137
37-year-old female with CN-AML had RUNX1 S318A (first amino acid of the transactivation domain), as well as NPM1 mutation, FLT3-ITD, DNMT3A mutation (non-R882), WT1 mutation, and TET2 mutation. The RUNX1 variant was found in the patient's germline, but not the NPM1 mutation (by buccal cell analysis). The patient didn't have a known history of bleeding or thrombocytopenia before the AML diagnosis or a family history (FDR only) of hematological problems. (Paper also cited in HGMD CM137025, which is DM? for AML.) PubMed:23753029
2 affected male relatives with primary immunodeficiency disease IX (neutrophil defect or congenital condition with bone marrow failure, such as dyskeratosis congenita and Fanconi-like phenotype, anemia, and thrombocytopenia) had G6PC3 variants and RUNX1 S318A. G6PC3 has been previously associated with congenital neutropenia (PMID: 19118303). RUNX1 S318A has been reported as a germline variant in an AML patient (PMID: 23753029). (Paper also cited in HGMD CM137025, which is DM? for AML.) PubMed:27577878
NM_001754.4(RUNX1):c.952T>G p.S318A (VAF=14.9%) detected in a patient with newly diagnosed AML. However, the patient also had NM_001754.4(RUNX1):c.954dupC p.S319fs (VAF=14.4%) and NM_001754.4(RUNX1):c.950T>G p.L317R (VAF=15.0%). PubMed:28933735
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
PP3
REVEL score=0.093, which is not >0.75 threshold.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
ALL:0.08130% (230/282886 alleles) - AMR:0.6377% (226) - OTH:0.04153% (3) - SAS:0.003266% (1) (gnomAD v2) ALL:0.01256% (18/143302 alleles) - AMR:0.1245% (17) - AFR:0.002379% (1) (gnomAD v3)
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 105-204.
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
Curation History
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