NM_001145661.1:c.953C>T (p.Ala318Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.1 Multiple in silico predictors support a deleterious effect on protein function, with REVEL score 0.952 and BayesDel score 0.604845, meeting PP3 at supporting strength.2 This variant is classified as Uncertain Significance in ClinVar (1 clinical laboratory, criteria provided, single submitter). No expert panel classification is available.3 PMID:22649106 reports functional characterization of a different substitution at the same residue (A318T) showing reduced CEBPA-mediated transcriptional activation in a somatic AML context, but the exact variant p.Ala318Val was not tested and cannot be used to meet PS3 or BS3.4 No CSPEC/VCEP framework exists for GATA2. Assessment follows generic ACMG/AMP 2015 rules (PMID:25741868) with final classification combining rules from the same source.5
GATA2
Final classification
VUS
GATA2 c.953C>T · p.Ala318Val
GATA2
NM_001145661.1:c.953C>T (p.Ala318Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
GATA2 c.953C>T
PM2 + PP3
→
VUS
2
revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_001145661.1 · variants mapped to exon structure
GATA2
NM_001145661.1
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2941214)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.952. BayesDel score = 0.604845.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GATA2, a transcription factor, is recurrently mutated in hematological malignancies and various solid tumors.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62003236, n = 29 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
22649106 ↗
GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia.
ONCOKB