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) | 0.0 | 7 bp |
| Donor Loss (DL) | 0.01 | -48 bp |
| Acceptor Gain (AG) | 0.1 | -18 bp |
| Donor Gain (DG) | 0.0 | -231 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'. The evidence for this variant shows: 'It is a missense change, not a null variant'. Therefore, this criterion is not applied because the variant does not result in a null allele.
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 previously established pathogenic variant results in A456V'. Therefore, this criterion is not applied because the amino acid change has not been 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'. The evidence for this variant shows: 'No data on de novo occurrence or parental testing'. Therefore, this criterion is not applied due to lack of de novo evidence.
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 studies have been performed on POLE A456V'. Therefore, this criterion is not applied because functional data are not available.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: 'No case-control or prevalence data in affected cohorts'. Therefore, this criterion is not applied due to absence of 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 for this variant shows: 'No evidence that residue A456 lies in a defined mutational hotspot or critical domain unique to POLE'. 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: 'Variant not found in population databases such as gnomAD (MAF = 0%)'. Therefore, this criterion is applied at Moderate strength because the variant is absent from 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 for this variant shows: 'No information on zygosity or trans configuration with another 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: 'A456V is a missense change without alteration of protein length'. Therefore, this criterion is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen'. The evidence for this variant shows: 'A different missense alteration at residue A456 has been reported as pathogenic'. Therefore, this criterion is applied at Moderate strength because a different pathogenic missense at this residue is documented.
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 for this variant shows: 'No de novo or parental data available'. 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'. The evidence for this variant shows: 'No segregation studies reported'. 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'. The evidence for this variant shows: 'Insufficient data on rate of benign missense in POLE and mechanism uncertainty'. 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 shows: 'In silico predictions are mixed and SpliceAI predicts no significant impact'. 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'. The evidence for this variant shows: 'No phenotype or family history data 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 evidence for this variant shows: 'Not reported in ClinVar or other databases'. 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'. The evidence for this variant shows: 'MAF = 0% in population databases'. 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 disorder'. The evidence for this variant shows: 'Absent from population databases; frequency is 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 disorder'. The evidence for this variant shows: 'No observations in healthy individuals reported'. 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'. The evidence for this variant shows: 'No functional studies 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'. The evidence for this variant shows: 'No family segregation data'. 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'. The evidence for this variant shows: 'POLE disease mechanism includes pathogenic missense variants'. 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'. The evidence for this variant shows: 'No data on cis/trans observations'. 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'. The evidence for this variant shows: 'A456V is 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: 'In silico predictions are mixed and SpliceAI predicts no significant splicing impact'. Therefore, this criterion is applied at Supporting strength because computational evidence does not predict a damaging 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 for this variant shows: 'No co-occurring molecular basis reported'. 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'. The evidence for this variant shows: 'Not reported as benign in any source'. 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 evidence for this variant shows: 'A456V is a missense change, not synonymous'. Therefore, this criterion is not applied.