POLE c.1372T>A, p.Tyr458Asn
NM_006231.4:c.1372T>A
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.636
Uncertain (High)
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
POLE
Transcript
NM_006231.4
MANE Select
Total Exons
49
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006231.2 | Alternative | 49 exons | Reverse |
| NM_006231.3 | RefSeq Select | 49 exons | Reverse |
Variant Details
HGVS Notation
NM_006231.4:c.1372T>A
Protein Change
Y458N
Location
Exon 14
(Exon 14 of 49)
5'
Exon Structure (49 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 458: Y458F, Y458H
Variant interpretation based on transcript NM_006231.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 458: Y458F, Y458H
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The POLE Y458N variant has not been functionally characterized.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.636
0.636
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
metasvm: D
metalr: D
primateai: D
Benign:
CADD: 4.10
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
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 a missense change (Y458N), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the definition for a null effect.
PS1
PS1 (Not Applied)
Strength Modified
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 does not demonstrate an identical amino acid change previously established as pathogenic. Therefore, this criterion is not applied at Not Applied strength.
PS2
PS2 (Not Applied)
Strength Modified
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 occurrence or parental testing data. Therefore, this criterion is not applied at Not Applied strength.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines for PS3, the finding is: 'The variant has not been functionally characterized'. The evidence for this variant confirms that no well-established functional studies are available to support a damaging effect. Therefore, this criterion is not applied at Not Applied strength.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals is significantly increased compared with controls'. The evidence for this variant does not show an increased prevalence in affected individuals. Therefore, this criterion is not applied at Not Applied strength.
PM1
PM1 (Not Applied)
Strength Modified
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 does not definitively place it in a singular mutational hot spot or exclusive functional domain. Therefore, this criterion is not applied at Not Applied strength.
PM2
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 a Minor Allele Frequency (MAF) of 0% and absence from population databases such as gnomAD. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
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 provides no data on presence in trans with another pathogenic variant. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied)
Strength Modified
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 indicates a missense change rather than an in-frame deletion/insertion or stop-loss. Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Moderate)
According to Standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen'. The evidence for this variant shows that while Y458N is novel, a different missense change at the same amino acid residue has been established as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied)
Strength Modified
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 does not provide any de novo information. Therefore, this criterion is not applied at Not Applied strength.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant does not include family segregation data. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied)
Strength Modified
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 does not provide a strong indication of gene constraint specifically for missense variants beyond what is already noted. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied)
Strength Modified
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 mixed computational predictions with indications of both damaging and benign effects, leading to an overall inconclusive impact. Therefore, this criterion is not applied at Not Applied strength.
PP4
PP4 (Not Applied)
Strength Modified
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 lacks detailed phenotype or family history correlation. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied)
Strength Modified
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, including ClinVar entries, classifies it as VUS and does not meet the criteria for PP5. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (stand-alone benign evidence)'. The evidence for this variant demonstrates a frequency of 0% in population databases. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows no occurrences in large population datasets. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant does not include such observations. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied)
Strength Modified
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 indicates that functional studies have not been performed or do not support a damaging effect. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant lacks segregation analysis data. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease'. The evidence for this variant does not support application of BP1 because POLE is known to have pathogenic missense variants as well. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied)
Strength Modified
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 does not indicate any such observation. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied)
Strength Modified
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 and not an in-frame deletion/insertion in a repetitive region. Therefore, this criterion is not applied at Not Applied strength.
BP4
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 mixed computational results; while some predictors (PolyPhen, MetaSVM, MetaLR, PrimateAI) indicate a damaging effect, the relatively low CADD score (4.10) and minimal splicing impact from SpliceAI (score 0.07) point toward a benign effect. Therefore, this criterion is applied at Supporting strength because the overall computational evidence leans toward a benign interpretation.
BP5
BP5 (Not Applied)
Strength Modified
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 does not include such an occurrence. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. Although ClinVar has entries of uncertain significance, the evidence does not fulfill BP6 criteria conclusively. Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows that it results in an amino acid substitution (Y458N) and is not synonymous. Therefore, this criterion is not applied at Not Applied strength.