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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.08 | 55 bp |
| Donor Loss (DL) | 0.02 | -35 bp |
| Acceptor Gain (AG) | 0.01 | -179 bp |
| Donor Gain (DG) | 0.01 | -156 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 for this variant shows it is a missense change (E329K), not a null variant. Therefore, this criterion is not applied because the variant does not meet the rule of being a null variant in a LoF gene.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows no known pathogenic variant resulting in E329K at POLE. Therefore, this criterion is not applied because there is no identical amino acid change previously established as pathogenic.
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'. There is no evidence of de novo occurrence for this variant. Therefore, this criterion is not applied due to lack of de novo data.
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 for this variant shows no functional characterization has been performed. Therefore, this criterion is not applied because functional data are absent.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. There is no case-control data showing enrichment of E329K in affected individuals. Therefore, this criterion is not applied due to lack of prevalence evidence.
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'. While E329K lies within the exonuclease domain of POLE, there is no specific evidence that position 329 is a known mutational hotspot with established pathogenic variation. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows it is absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is not observed 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'. There is no evidence of E329K observed in trans with a known pathogenic POLE variant. Therefore, this criterion is not applied.
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 for this variant shows a single amino acid substitution with no change in protein length. Therefore, this criterion is not applied.
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'. There is no known pathogenic variant at residue E329 in POLE. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. There is no evidence of assumed de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. There are no segregation data available for this variant. Therefore, this criterion is not applied.
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'. While POLE missense variants can be pathogenic, there is insufficient evidence regarding the background rate of benign missense variants in POLE. Therefore, this criterion is not applied.
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'. The evidence for this variant from in silico tools is predominantly benign and SpliceAI shows no significant splicing effect. Therefore, this criterion is not applied.
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'. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The variant is not reported in ClinVar or other databases as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (stand-alone)'. The variant is absent from population databases, not above any high‐frequency threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The variant frequency is 0% in gnomAD, not greater than expected. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant (with full penetrance) disorder'. There are no reports of this variant in healthy individuals. Therefore, this criterion is not applied.
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'. No functional studies are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. No segregation analysis has been performed. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. POLE disease mechanisms include missense variants in the exonuclease domain. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. There is no evidence of cis/trans occurrence with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. This variant is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
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'. The evidence for this variant shows benign predictions from CADD, PolyPhen, MetaSVM and SpliceAI score of 0.08. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict no deleterious 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'. There is no such case information. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. No reputable source reports this variant as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The variant is non-synonymous. Therefore, this criterion is not applied.