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) and as Likely benign (2 clinical laboratories) and as Benign (1 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 | -26 bp |
| Donor Loss (DL) | 0.0 | -51 bp |
| Acceptor Gain (AG) | 0.06 | -6 bp |
| Donor Gain (DG) | 0.0 | 381 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 (F837S), 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 causing the same F837S change. Therefore, this criterion is not applied at Not Applied strength because there is no matching pathogenic 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 parental testing or de novo status data available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence has not been demonstrated.
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 F837S. Therefore, this criterion is not applied at Not Applied strength because there are no functional study data.
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 at Not Applied strength because increased prevalence in cases has not been demonstrated.
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 F837 lies in a mutational hotspot or a critical functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a recognized hotspot or domain.
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: MAF=0.0269% in gnomAD (76/282,762 alleles), extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency 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 information on phasing or trans configuration. Therefore, this criterion is not applied at Not Applied strength because trans configuration with a pathogenic variant is not known.
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 alteration of protein length. Therefore, this criterion is not applied at Not Applied strength because there is no change in 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 changes reported at residue F837. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variant at the same residue is known.
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 data on de novo occurrence. Therefore, this criterion is not applied at Not Applied strength because de novo status is not assessed.
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 because segregation has not been evaluated.
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 missense constraint and disease mechanism. Therefore, this criterion is not applied at Not Applied strength because the gene-specific missense context is unclear.
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: computational tools (REVEL 0.12, CADD, PolyPhen-2, MetaSVM, MetaLR) predict benign impact. 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 or family history provided. Therefore, this criterion is not applied at Not Applied strength because phenotype 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: no reputable source reports this variant as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no pathogenic reputation exists.
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=0.0269%, well below >5% threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not above the stand-alone 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: MAF=0.0269% is not above the expected threshold for POLE-related disease. Therefore, this criterion is not applied at Not Applied strength because frequency is not higher than expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: heterozygotes observed in gnomAD but no data on health status or penetrance. Therefore, this criterion is not applied at Not Applied strength because healthy carrier status cannot be confirmed.
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 effect has not been tested.
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 analysis. Therefore, this criterion is not applied at Not Applied strength because family segregation is unavailable.
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 is not solely loss-of-function. Therefore, this criterion is not applied at Not Applied strength because missense variants can be disease-causing.
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 information on co-occurrence with other variants. Therefore, this criterion is not applied at Not Applied strength because phasing data are not available.
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: this is a missense change. Therefore, this criterion is not applied at Not Applied strength because it is not an 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: REVEL score 0.12 (<0.15 threshold), CADD, PolyPhen-2, MetaSVM, MetaLR predict benign impact, SpliceAI 0.06 indicates minimal splicing effect. 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 case reports with an alternate genetic diagnosis. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
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: while some ClinVar submissions list likely benign or benign, accessible supporting evidence is lacking. Therefore, this criterion is not applied at Not Applied strength because detailed benign evidence is not available.
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, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.