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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001754.4(RUNX1):c.1196G>T (p.Ser399Ile)

CA320251372

532658 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c7f454da-b262-4987-a3b3-f3d8bfd3c4e1
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_001754.4:c.1196G>T
NM_001754.4(RUNX1):c.1196G>T (p.Ser399Ile)
NC_000021.9:g.34792382C>A
CM000683.2:g.34792382C>A
NC_000021.8:g.36164679C>A
CM000683.1:g.36164679C>A
NC_000021.7:g.35086549C>A
NG_011402.2:g.1197330G>T
ENST00000675419.1:c.1196G>T
ENST00000300305.7:c.1196G>T
ENST00000344691.8:c.1115G>T
ENST00000399240.5:c.923G>T
ENST00000437180.5:c.1196G>T
ENST00000482318.5:c.*786G>T
NM_001001890.2:c.1115G>T
NM_001001890.3:c.1115G>T
NM_001754.5:c.1196G>T
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Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 25
BP5 BP7 BP2 BP3 BP1 PS2 PS3 PS1 PS4 PP1 PP4 PP3 PP2 PM5 PM1 PM3 PM4 PM6 PM2 PVS1 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.4(RUNX1):c.1196G>T (p.Ser399Ile) is a missense variant which has a REVEL score < 0.50 (0.116) 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). The variant has been published in a pediatric patient with B-ALL, which was confirmed to be in the germline based on assessment in a remission sample (PMID: 34166225). It was also identified in a male patient with primary myelofibrosis, but the germline assessment was based on a buccal mucosa sample (PMID: 31135094), and in a 58-year-old Greek patient with ovarian cancer who also carried RAD51C c.90del/p.F32Sfs*8 (LOVD: Individual #00021433). However, PS4_supporting cannot be applied because the variant presents more than 2 times in gnomAD (5 heterozygotes in v2 and 1 heterozygote in v3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4.
Met criteria codes
BP4
REVEL score = 0.116, 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
BP5
Not applicable
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
BP3
Not applicable
BP1
Not applicable
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
Expression of the mutant protein was demonstrated in vitro (Fig. S1), and transactivation of the SPI1 promoter in HeLa cells using a luciferase reporter assay was 71.55% of WT (Table S10) (PMID: 34166225).
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
The variant has been published in a pediatric patient with B-ALL, which was confirmed to be in the germline based on assessment in a remission sample (PMID: 34166225). It was also identified in a male patient with primary myelofibrosis who also had germline JAK2 N1108S and somatic ASXL1 and ZRSR2 alterations, but this assessment was based on buccal mucosa sample (PMID: 31135094). Finally, the variant was identified in a 58yo Greek patient with ovarian cancer who also carried RAD51C c.90del/p.F32Sfs*8 (LOVD:Individual #00021433).
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP3
REVEL score = 0.116, 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
PM5
S399N/S372N has been reported the most in Mastermind, but data is likely insufficient for LP/P classification.
PM1
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204) or within residues 89-204.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM2
gnomAD (v2): ALL: 0.002893% (5/172810) - AMR: 0.01154% (3/25986) - NFE: 0.001420% (1/70420) - OTH: 0.02134% (1/4686) gnomAD (v3): ALL: 0.0006585 (1/151858) - AMR: 0.006545% (1/15278)
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
gnomAD (v2): ALL: 0.002893% (5/172810) - AMR: 0.01154% (3/25986) - NFE: 0.001420% (1/70420) - OTH: 0.02134% (1/4686) gnomAD (v3): ALL: 0.0006585 (1/151858) - AMR: 0.006545% (1/15278)
BS2
Not applicable
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
Expression of the mutant protein was demonstrated in vitro (Fig. S1), and transactivation of the SPI1 promoter in HeLa cells using a luciferase reporter assay was 71.55% of WT (Table S10) (PMID: 34166225).
BS1
gnomAD (v2): ALL: 0.002893% (5/172810) - AMR: 0.01154% (3/25986) - NFE: 0.001420% (1/70420) - OTH: 0.02134% (1/4686) gnomAD (v3): ALL: 0.0006585 (1/151858) - AMR: 0.006545% (1/15278)
Curation History
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