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""
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 | 7 bp |
| Donor Loss (DL) | 0.01 | -48 bp |
| Acceptor Gain (AG) | 0.1 | -18 bp |
| Donor Gain (DG) | 0.0 | -231 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – 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 (c.1367C>T, p.A456V), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not predicted to result in loss of function.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – 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 yields the same A456V amino acid change. Therefore, this criterion is not applied at Not Applied strength because there is no identical amino acid change previously classified as pathogenic.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – 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 unconfirmed.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – 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 p.A456V. Therefore, this criterion is not applied at Not Applied strength because functional assay data are lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – 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 statistical enrichment data are unavailable.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: residue A456 is not documented as a mutational hot spot and no domain-specific constraint information is available. Therefore, this criterion is not applied at Not Applied strength because there is no evidence for a critical functional domain annotation.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: not found in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on phase with other variants. Therefore, this criterion is not applied at Not Applied strength because trans observation data are missing.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a single amino acid substitution without change in protein length. Therefore, this criterion is not applied at Not Applied strength.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: another missense change at residue A456 has been previously determined to be pathogenic. Therefore, this criterion is applied at Moderate strength because this novel change affects a residue with established pathogenic missense variation.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no information on assumed de novo occurrence. Therefore, this criterion is not applied at Not Applied strength because de novo data without parentage confirmation are unavailable.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – 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 analysis is not available.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – 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 gene-specific missense constraint or frequency of benign missense variants. Therefore, this criterion is not applied at Not Applied strength.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – Multiple lines of computational evidence support a deleterious effect on the gene or gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: mixed in silico predictions with overall benign tendency and no significant splicing impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not consistently support pathogenicity.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – 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 clinical presentation data. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unknown.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other expert panels. Therefore, this criterion is not applied at Not Applied strength because no reputable source classification is available.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder (e.g., >5%)". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because population frequency is not above the threshold.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because population frequency is not greater than expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: no reports in healthy individuals. 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: "BS3 – 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 because functional evidence is unavailable.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – 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 available.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only loss of function causes disease". The evidence for this variant shows: POLE-associated disease mechanisms include pathogenic missense variants. Therefore, this criterion is not applied at Not Applied strength because missense is a known disease mechanism.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – 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 phase information. Therefore, this criterion is not applied at Not Applied strength because phase data are missing.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: mixed in silico predictions with majority benign and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence overall suggests no functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with alternate molecular diagnoses. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: not reported in any database or expert panel. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense, not synonymous. Therefore, this criterion is not applied at Not Applied strength.