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 | 320 bp |
| Donor Loss (DL) | 0.0 | 245 bp |
| Acceptor Gain (AG) | 0.0 | 101 bp |
| Donor Gain (DG) | 0.0 | 195 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 (R712C), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant.
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 codon 712 resulting in R712C. Therefore, this criterion is not applied at Not Applied strength because there is no prior pathogenic variant with the same amino acid change.
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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status is not confirmed.
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 for POLE R712C. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
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 demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength 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: R712 is not known to lie in a mutational hot spot or critical domain lacking benign variation. Therefore, this criterion is not applied at Not Applied strength.
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: extremely rare in population databases (gnomAD MAF = 0.000806%, 2/248264 alleles, no homozygotes). Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in 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 trans configuration with another pathogenic variant. Therefore, this criterion is not applied at Not Applied strength 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 for this variant shows: it is a missense substitution without protein length change. Therefore, this criterion is not applied at Not Applied strength.
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 codon 712. Therefore, this criterion is not applied at Not Applied strength.
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 information on de novo occurrence. Therefore, this criterion is not applied at Not Applied strength.
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 family segregation data. Therefore, this criterion is not applied at Not Applied strength.
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: POLE has both benign and pathogenic missense variants, and R712C does not fall in a well-established missense-critical region. Therefore, this criterion is not applied at Not Applied strength.
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 for this variant shows: in silico predictions are mixed but overall benign (CADD 4.94, REVEL 0.26, SpliceAI 0). Therefore, this criterion is not applied at Not Applied strength due to lack of consistent pathogenic computational evidence.
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 at Not Applied strength.
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 reports it as VUS by multiple labs, not pathogenic. Therefore, this criterion is not applied at Not Applied strength.
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 = 0.000806%, which is below benign threshold. Therefore, this criterion is not applied at Not Applied strength.
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: MAF is well below any maximum credible frequency. Therefore, this criterion is not applied at Not Applied strength.
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 for this variant shows: no specific healthy adult observation data. Therefore, this criterion is not applied at Not Applied strength.
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 performed. Therefore, this criterion is not applied at Not Applied strength.
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 at Not Applied strength.
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 dominant-negative and missense effects, so not only LoF. Therefore, this criterion is not applied at Not Applied strength.
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 data with other variants. Therefore, this criterion is not applied at Not Applied strength.
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. Therefore, this criterion is not applied at Not Applied strength.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: in silico predictors (CADD 4.94, REVEL 0.26, SpliceAI 0) indicate no impact on function or splicing. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict 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 for this variant shows: no cases with an alternate molecular diagnosis. Therefore, this criterion is not applied at Not Applied strength.
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 has reported it as benign. Therefore, this criterion is not applied at Not Applied strength.
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 not synonymous but missense. Therefore, this criterion is not applied at Not Applied strength.