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"This variant has been reported in ClinVar as Uncertain significance (4 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 | -465 bp |
| Donor Loss (DL) | 0.0 | 104 bp |
| Acceptor Gain (AG) | 0.0 | 327 bp |
| Donor Gain (DG) | 0.01 | 218 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 rather than a null variant. Therefore, this criterion is not applied because the variant does not meet PVS1 requirements.
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 for this variant shows no previously established pathogenic D275H change. Therefore, this criterion is not applied because there is no identical amino acid change reported 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 de novo segregation data. 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 for this variant shows no functional assay data. Therefore, this criterion is not applied because no functional studies are 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 cohort data. Therefore, this criterion is not applied because prevalence data are not available.
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 data identifying a mutational hot spot or known domain at residue D275. Therefore, this criterion is not applied because location is not established as PM1.
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. Therefore, this criterion is applied at Moderate strength because the variant meets the absence criteria.
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 trans data in a recessive context. Therefore, this criterion is not applied because PM3 is not relevant for this dominant context and no trans observations exist.
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 it is a missense change without length alteration. Therefore, this criterion is not applied because PM4 requires protein length change.
PM5 (Moderate)
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 for this variant shows other missense changes at residue D275 have been reported as pathogenic. Therefore, this criterion is applied at Moderate strength because the residue is known to be sensitive to missense changes.
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 data. Therefore, this criterion is not applied due to lack of assumed de novo data.
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. Therefore, this criterion is not applied because family segregation data are unavailable.
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 missense constraint for POLE. Therefore, this criterion is not applied because gene-specific missense constraint is uncharacterized.
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 mixed in silico predictions with some tools predicting pathogenicity and others benign. Therefore, this criterion is not applied because computational evidence is conflicting.
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 detailed phenotype or family history. Therefore, this criterion is not applied because phenotype specificity data are lacking.
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 ClinVar entries as VUS, not pathogenic. Therefore, this criterion is not applied because no reputable source classifies it as pathogenic.
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 for this variant shows a frequency of 0%. Therefore, this criterion is not applied because frequency is not above the BA1 threshold.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows it is absent from population databases. Therefore, this criterion is not applied because frequency does not exceed expected rates.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows no such observations. Therefore, this criterion is not applied because BS2 data are unavailable.
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. Therefore, this criterion is not applied because functional assay data are lacking.
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 segregation data. Therefore, this criterion is not applied because family data are not provided.
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 missense changes. Therefore, this criterion is not applied because missense is a known mechanism.
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 for this variant shows no such observations. Therefore, this criterion is not applied due to lack of phase data.
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 it is a missense change. Therefore, this criterion is not applied because BP3 applies only to in-frame indels.
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 mixed in silico predictions with SpliceAI predicting no splicing impact and several tools indicating benign. Therefore, this criterion is applied at Supporting strength because computational evidence leans toward no functional impact.
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 alternate molecular basis in reported cases. Therefore, this criterion is not applied due to lack of 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 for this variant shows no reputable benign assertions. Therefore, this criterion is not applied because no such reports exist.
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 it is a missense change. Therefore, this criterion is not applied because BP7 applies only to synonymous variants.