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
OpenVariant summary: POLE c.4529_4530delinsTG (p.Ala1510Val) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277818 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4529_4530delinsTG has been reported in the literature in an individual affected with Colon Cancer without confirmation of germline inheritance (Garmezy_2022). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35108036). ClinVar contains an entry for this variant (Variation ID: 576750). Based on the evidence outlined above, the variant was classified as uncertain significance.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely 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 | -163 bp |
| Donor Loss (DL) | 0.0 | -21 bp |
| Acceptor Gain (AG) | 0.0 | 47 bp |
| Donor Gain (DG) | 0.0 | 3 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LoF is a known mechanism of disease." The evidence for this variant shows: a missense change (c.4529_4530delinsTG resulting in A1510V) rather than 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 previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant resulting in A1510V. Therefore, this criterion is not applied at Not Applied strength because there is no known 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 de novo status or pedigree information is available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence cannot be 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 characterization studies have been performed. 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 prevalence data in affected individuals are available. Therefore, this criterion is not applied at Not Applied strength because case frequency data are absent.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or well-established functional domain without benign variation." The evidence for this variant shows: domain annotation or mutational hotspot data are not provided. Therefore, this criterion is not applied at Not Applied strength because location within a critical domain cannot be assessed.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: absent from population databases including gnomAD. Therefore, this criterion is applied at Moderate strength because the variant is not observed in large-scale controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: zygosity and trans configuration data are not available. Therefore, this criterion is not applied at Not Applied strength because trans allele information is missing.
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: the change is a missense substitution without alteration of protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length change.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is established as pathogenic." The evidence for this variant shows: no other pathogenic missense changes at residue A1510 have been reported. Therefore, this criterion is not applied at Not Applied strength because there is no precedent of a pathogenic variant at this residue.
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: de novo status is not documented. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence 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 segregation data are available. Therefore, this criterion is not applied at Not Applied strength because familial 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: gene-specific missense constraint data are not provided. Therefore, this criterion is not applied at Not Applied strength because gene-level missense variation rates are unknown.
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 or gene product." The evidence for this variant shows: computational predictions are mixed with benign PolyPhen and SpliceAI indicating no splicing impact. Therefore, this criterion is not applied at Not Applied strength because the in silico evidence is conflicting.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: phenotype or clinical correlation data are not available. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
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 are predominantly VUS or likely benign. Therefore, this criterion is not applied at Not Applied strength because no reputable source reports this variant as pathogenic.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is greater than 5% in control populations." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied at Not Applied strength because the frequency is well below 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: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength because the variant is not present above disorder-specific thresholds.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals with full penetrance expected at an early age." The evidence for this variant shows: no data on occurrence in healthy adults. Therefore, this criterion is not applied at Not Applied strength because absence of healthy control observations 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 have been performed. Therefore, this criterion is not applied at Not Applied strength 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 are available. Therefore, this criterion is not applied at Not Applied strength because familial segregation has not been assessed.
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: disease mechanism for POLE germline variants is not solely loss-of-function. Therefore, this criterion is not applied at Not Applied strength because the gene’s disease mechanism does not support this rule.
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: phasing information is not available. Therefore, this criterion is not applied at Not Applied strength because allelic phase cannot be determined.
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 in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type is not applicable.
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 (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: in silico predictors are mixed but overall suggest no damaging effect, with SpliceAI predicting no impact on splicing. Therefore, this criterion is applied at Supporting strength because computational analyses do not predict a deleterious 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 alternate molecular diagnoses have been reported in cases. Therefore, this criterion is not applied at Not Applied strength because no such case context exists.
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: ClinVar submissions are VUS or likely benign, but none qualify as a clearly reputable source reporting benign without evidence. 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. Therefore, this criterion is not applied at Not Applied strength because the variant is missense.