POLE c.4276G>A, p.Val1426Ile
NM_006231.4:c.4276G>A
COSMIC ID: COSM6000864
Variant of Uncertain Significance (VUS)
The variant NM_006231.4:c.4276G>A (p.V1426I) in POLE is classified as a Variant of Uncertain Significance due to the presence of moderate evidence for pathogenicity (PM2) and supporting evidence for benign impact (BP4), which conflict and are insufficient for classification as Likely Pathogenic or Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
POLE
Transcript
NM_006231.4
MANE Select
Total Exons
49
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006231.2 | Alternative | 49 exons | Reverse |
| NM_006231.3 | RefSeq Select | 49 exons | Reverse |
Variant Details
HGVS Notation
NM_006231.4:c.4276G>A
Protein Change
V1426I
Location
Exon 33
(Exon 33 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1426 in gene POLE
Alternate Identifiers
COSM6000864
Variant interpretation based on transcript NM_006231.4
Genome Browser
Loading genome browser...
HGVS InputNM_006231:c.4276G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.00566%
Rare
Highest in Population
East Asian
0.0401%
Low Frequency
Global: 0.00566%
East Asian: 0.0401%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282534Alt: 16Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00566%, 16/282534 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0401%, 8/19950 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1426 of the POLE protein (p.Val1426Ile). This variant is present in population databases (rs775072147, gnomAD 0.03%). This missense change has been observed in individual(s) with POLE-related conditions (PMID: 32522261). ClinVar contains an entry for this variant (Variation ID: 405845). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
BP4
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1426 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.186
0.186
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.29polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence shows: this variant is a missense change (p.V1426I) and does not introduce a null allele. Therefore, this criterion is not applied because the variant does not result in a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence shows: there is no reported pathogenic variant resulting in the V1426I amino acid change. Therefore, this criterion is not applied because the variant does not match a known pathogenic amino acid substitution.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence shows: no de novo occurrence has been documented. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence shows: no functional studies have been performed for this variant. Therefore, this criterion is not applied because functional impact has not been demonstrated.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence shows: no case-control or prevalence data in affected individuals. Therefore, this criterion is not applied due to absence of comparative prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence shows: p.V1426I is not known to reside in a recognized mutational hotspot or critical functional domain. Therefore, this criterion is not applied because no hotspot or critical domain involvement is evident.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence shows: the variant has a minor allele frequency of 0.00566% in gnomAD, which is below 0.1%. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence shows: no observations of this variant in trans with a known pathogenic allele. Therefore, this criterion is not applied because trans configuration data are lacking.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence shows: this is a missense change without alteration of protein length. Therefore, this criterion is not applied because there is no change in protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence shows: no other pathogenic missense variants have been reported at residue V1426. Therefore, this criterion is not applied due to lack of precedent pathogenic changes at this position.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows: no evidence of an assumed de novo event. Therefore, this criterion is not applied due to absence of de novo assumptions.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence shows: no familial segregation data are available. Therefore, this criterion is not applied due to lack of segregation evidence.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence shows: insufficient data on POLE gene missense constraint and variant distribution to support low benign variation rate. Therefore, this criterion is not applied due to lack of gene-specific missense constraint information.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence shows: in silico tools (CADD, PolyPhen-2, MetaSVM, MetaLR, PrimateAI, REVEL) predict benign and SpliceAI indicates no splicing impact. Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence shows: no phenotype or family history data are provided. Therefore, this criterion is not applied due to absence of phenotype specificity.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence shows: ClinVar submissions report this variant as VUS or likely benign, with no pathogenic assertions without evidence. Therefore, this criterion is not applied because no reputable pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence shows: allele frequency is 0.00566%, well below any high-frequency threshold. Therefore, this criterion is not applied because the variant is too rare to meet BA1.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence shows: allele frequency does not exceed expected disease thresholds. Therefore, this criterion is not applied because frequency is not higher than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence shows: no data on observation in healthy, fully penetrant individuals. Therefore, this criterion is not applied due to lack of healthy adult observation data.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence shows: no functional assays have been conducted. Therefore, this criterion is not applied because functional benign evidence is absent.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence shows: no segregation studies are available. Therefore, this criterion is not applied due to absence of segregation data.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence shows: POLE disease mechanism involves pathogenic missense variants. Therefore, this criterion is not applied because missense variants are known to cause disease in this gene.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence shows: no observations of this variant in cis or trans with a pathogenic allele. Therefore, this criterion is not applied due to lack of such observations.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence shows: this variant is a single-nucleotide missense change, not an in-frame indel. Therefore, this criterion is not applied because the variant type does not match.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. The evidence shows: in silico predictors (CADD, PolyPhen-2, MetaSVM, MetaLR, PrimateAI, REVEL) predict benign, and SpliceAI predicts no splicing impact (score 0.01). Therefore, this criterion is applied at Supporting strength because multiple computational tools support a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence shows: no cases reported with an alternate molecular diagnosis. Therefore, this criterion is not applied due to absence of such case data.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence shows: ClinVar includes one likely benign assertion but lacks detailed evidence. Therefore, this criterion is not applied because a well-documented benign report without accessible evidence is not present.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence shows: this is a missense variant, not synonymous. Therefore, this criterion is not applied because the variant is not synonymous.