Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis 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
"This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 71 bp |
| Donor Loss (DL) | 0.01 | -134 bp |
| Acceptor Gain (AG) | 0.0 | 175 bp |
| Donor Gain (DG) | 0.0 | 127 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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 (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 (Not Applied)
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 (Not Applied)
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 (Not Applied)
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.