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 Likely benign (6 clinical laboratories) and as Benign (1 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 | 442 bp |
| Donor Loss (DL) | 0.0 | -29 bp |
| Acceptor Gain (AG) | 0.0 | 393 bp |
| Donor Gain (DG) | 0.0 | -487 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: c.1197G>A (p.A399=) is a synonymous variant not predicted to introduce a premature stop codon or affect canonical splice sites. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the definition of 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: p.Ala399 remains alanine, and there is no report of any pathogenic variant causing the same amino acid change at this codon. Therefore, this criterion is not applied at Not Applied strength because no known pathogenic amino acid change matches.
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 data are not available.
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 assays have been performed for c.1197G>A. Therefore, this criterion is not applied at Not Applied strength because functional data are 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 reporting enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because prevalence data are not available.
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: codon 399 is not known as a mutational hotspot or within a well-established functional domain critical for POLE function. 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: c.1197G>A is not observed in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large population cohorts.
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 any pathogenic POLE variant. Therefore, this criterion is not applied at Not Applied strength.
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: c.1197G>A is synonymous and does not change protein length. 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: p.Ala399 is unchanged and no pathogenic missense at this residue is reported. 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 assumed de novo data. 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 segregation data in families. 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: this is a synonymous change, not a missense variant. 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". The evidence for this variant shows: in silico tools including CADD and SpliceAI predict no deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support damage.
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.
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 benign/likely benign, 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". The evidence for this variant shows: allele frequency is 0% in gnomAD, not high. 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: allele frequency is absent, not greater than expected. 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 data on observation in healthy individuals. 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 have been 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: this is a synonymous change, not a missense. 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 phase data. 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: 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: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: in silico tools (CADD score 0.05, SpliceAI score 0.00) predict no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a 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 cases reported with alternate molecular diagnoses. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Supporting)
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 entries from multiple laboratories classify it as Benign/Likely benign. Therefore, this criterion is applied at Supporting strength because reputable clinical laboratories report a benign interpretation.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: c.1197G>A is synonymous and SpliceAI predicts no splicing impact (score 0.00). Therefore, this criterion is applied at Supporting strength because it is a silent change without splicing effect.