The variant is located at codon 2 (p.Pro2Leu), a statistically significant mutational hotspot residue in EIF1AX, a well-established driver gene in uveal melanoma (PM1_moderate).1 The variant is completely absent from gnomAD v4.1 (0/1,155,341 alleles), gnomAD v2.1, and gnomAD Canada, meeting the PM2 criterion for absence from population databases (PM2_moderate).2 BayesDel predicts a benign score of -0.368928, and SpliceAI predicts no splice impact (max delta 0.00), providing multiple lines of computational evidence against a damaging effect (BP4_supporting).3 No functional studies, de novo reports, segregation data, or ClinVar classifications exist for this variant. PS3, PS2, PP1, PP5, and BS3 are not met. PVS1, PM5, and BP7 are not applicable to this missense variant.
EIF1AX
Final classification
VUS
EIF1AX c.5C>T · p.Pro2Leu
EIF1AX
The variant is located at codon 2 (p.Pro2Leu), a statistically significant mutational hotspot residue in EIF1AX, a well-established driver gene in uveal melanoma (PM1_moderate).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2
BP4
VUS
EIF1AX c.5C>T
PM1 + PM2 + BP4
→
VUS
Gene diagram
· NM_001412.4 · variants mapped to exon structure
EIF1AX
NM_001412.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 19 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant is located at codon 2 (p.Pro2Leu) in EIF1AX, a residue within a statistically significant mutational hotspot identified by cancerhotspots.org. EIF1AX is a well-established driver gene in uveal melanoma, and the N-terminal region encompassing codon 2 is critical for translation initiation function. The variant is completely absent from gnomAD, consistent with a functionally constrained residue.
cancerhotspots.org: P2 residue in a statistically significant hotspotCOSMIC: 7 somatic observations at this positionOncoKB: Likely Oncogenic
✓
PM2
moderate
Pathogenic
This variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,155,341 alleles (AF=0.00%), gnomAD v2.1 reports absence, and gnomAD Canada reports absence. The allele frequency of 0% is well below the PM2 threshold of <0.1%.
gnomAD v4.1: 0/1155341 alleles (AF=0.00%)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no damaging effect. BayesDel predicts a benign score of -0.368928 (well below the deleterious threshold of 0.27), integrating conservation, evolutionary, and biochemical features. SpliceAI predicts no splice impact (max delta score 0.00).
BayesDel: -0.368928 (benignintegrating 46 features)SpliceAI: max delta 0.00 (no predicted splice alteration).
Assessed · not applied
Pathogenic
PS1
No prior pathogenic variant with the same amino acid change (P2L) has been established in ClinVar or the literature.
PS2
No de novo occurrence data with confirmed paternity and maternity is available for this variant.
PS3
No well-established in vitro or in vivo functional studies directly testing this variant were identified.
PS4
No case-control data comparing variant prevalence in affected versus unaffected individuals is available.
PM6
No de novo occurrence data (without confirmed paternity and maternity) is available for this variant.
PP1
No cosegregation data in affected family members is available for this variant.
PP2
Insufficient constraint data to determine whether EIF1AX has a low rate of benign missense variation.
PP3
Computational evidence does not support a deleterious effect.
PP4
No patient phenotype or family history data is available to assess specificity for a disease with a single genetic etiology.
PP5
This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source.
Benign
BA1
The variant allele frequency is 0.00% in gnomAD v4.1 (0/1,155,341 alleles), far below the BA1 threshold of >1%.
BS1
The variant allele frequency is 0.00% in gnomAD v4.1, far below the BS1 threshold of >0.3%.
BS2
No data on observation in healthy adult individuals for a fully penetrant disorder is available.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant are available.
BS4
No segregation data in affected family members is available to assess lack of segregation.
BP1
EIF1AX is an oncogene in which missense variants are the primary established disease mechanism, not a gene where primarily truncating variants cause disease.
BP2
No data on observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, is available.
BP5
No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6
This variant is absent from ClinVar and has not been reported as benign by any reputable source.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1155341 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/55330 alleles, homozygotes = 0).
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 / 1,155,341
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.368928.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65451032, n = 7 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links