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 (7 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 | 88 bp |
| Donor Loss (DL) | 0.04 | -2 bp |
| Acceptor Gain (AG) | 0.0 | -354 bp |
| Donor Gain (DG) | 0.02 | -5 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 or multi-exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (T1771M), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce a null allele.
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 variant at residue T1771. Therefore, this criterion is not applied at Not Applied strength because there is no precedent pathogenic missense at this position.
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 data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assessed.
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. Therefore, this criterion is not applied at Not Applied strength because functional impact data are missing.
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 are available. Therefore, this criterion is not applied at Not Applied strength because prevalence in cases versus controls is unknown.
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 information places T1771 in a recognized hotspot or critical functional domain. Therefore, this criterion is not applied at Not Applied strength because domain/hotspot relevance cannot be established.
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: present in gnomAD at MAF=0.00399% with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
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 data on allelic phase with other variants. Therefore, this criterion is not applied at Not Applied strength because trans configuration cannot be assessed.
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 substitution without length change. Therefore, this criterion is not applied at Not Applied strength because it does not alter 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 for this variant shows: no other pathogenic missense variants reported at residue T1771. Therefore, this criterion is not applied at Not Applied strength because no alternative pathogenic variant at this position exists.
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 parental data available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assumed.
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 familial segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is lacking.
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 POLE gene missense constraint and mechanism. Therefore, this criterion is not applied at Not Applied strength due to lack of gene‐specific 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". The evidence for this variant shows: in silico predictors trend benign and SpliceAI score is low. Therefore, this criterion is not applied at Not Applied strength 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 for this variant shows: no clinical phenotype data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unavailable.
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 report VUS only. Therefore, this criterion is not applied at Not Applied strength because no reputable source cites 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: MAF=0.00399%, well below the >5% threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not high enough.
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: MAF is well below disease‐specific thresholds. Therefore, this criterion is not applied at Not Applied strength because frequency is not too high.
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 data confirming presence in phenotyped healthy adults. Therefore, this criterion is not applied at Not Applied strength because healthy adult observations are lacking.
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 at Not Applied strength because functional assays are absent.
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 at Not Applied strength because segregation analysis is not performed.
BP1 (Not Applied)
According to standard ACMG guidelines the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: POLE disease mechanisms include missense variants. Therefore, this criterion is not applied at Not Applied strength 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 cis/trans phasing data. Therefore, this criterion is not applied at Not Applied strength because allelic configuration is unknown.
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 substitution, not an indel. Therefore, this criterion is not applied at Not Applied strength because the variant type is not in-frame indel.
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‐leaning in silico predictions and SpliceAI score of 0.04. Therefore, this criterion is applied at Supporting strength because computational evidence favors 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 case reports with alternative diagnoses. Therefore, this criterion is not applied at Not Applied strength because case context is unavailable.
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 source classifies it as benign. Therefore, this criterion is not applied at Not Applied strength because no such report exists.
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 variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.