POLE c.4448G>C, p.Ser1483Thr
NM_006231.4:c.4448G>C
Variant of Uncertain Significance (VUS)
This missense variant (p.Ser1483Thr) in POLE is absent from population databases (PM2) and computational evidence supports no impact (BP4). No additional pathogenic or benign criteria apply. Therefore, it remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
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.4448G>C
Protein Change
S1483T
Location
Exon 35
(Exon 35 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1483 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.4448G>C
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
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
No evidence of other pathogenic variants at position 1483 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.221
0.221
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.15polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease'. The evidence for this variant shows: it is a missense change (p.Ser1483Thr), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not produce a null allele.
PS1
PS1 (Not Applied) Strength Modified
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 results in p.Ser1483Thr. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
PS3
PS3 (Not Applied) Strength Modified
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. Therefore, this criterion is not applied at Not Applied strength because functional assay data are lacking.
PS4
PS4 (Not Applied) Strength Modified
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 are available. Therefore, this criterion is not applied at Not Applied strength because there is no statistical evidence of enrichment in affected individuals.
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 shows: p.Ser1483 is not within a known POLE mutational hotspot or critical functional domain. Therefore, this criterion is not applied at Not Applied strength because the residue is not in a recognized hotspot or domain.
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: it is not found in population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large population cohorts.
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 shows: no information on phase or presence of a second pathogenic allele. Therefore, this criterion is not applied at Not Applied strength because trans configuration data are unavailable.
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 shows: it is a single amino acid substitution without length change. Therefore, this criterion is not applied at Not Applied strength because there is no alteration in protein length.
PM5
PM5 (Not Applied) Strength Modified
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 variants reported at residue Ser1483. Therefore, this criterion is not applied at Not Applied strength because the residue has no known pathogenic missense substitutions.
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 shows: no de novo information or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status remains unassessed.
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 shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is unavailable.
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 shows: POLE has known pathogenic missense variants but this position is outside key domains and benign variation rate is unclear. Therefore, this criterion is not applied at Not Applied strength due to insufficient context on missense variation rates.
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: in silico tools (CADD, PolyPhen-2, REVEL 0.22) and SpliceAI (0.03) predict no deleterious impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support a damaging effect.
PP4
PP4 (Not Applied) Strength Modified
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 phenotype or clinical context provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity data are lacking.
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 shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength because no reputable pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
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. Therefore, this criterion is not applied at Not Applied strength because the variant is not common.
BS1
BS1 (Not Applied) Strength Modified
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 frequency is not above expected thresholds.
BS2
BS2 (Not Applied) Strength Modified
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 reports of observation in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because no healthy cohort data exist.
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 shows: no functional assays have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional evidence is unavailable.
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 shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation information is missing.
BP1
BP1 (Not Applied) Strength Modified
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 is driven by pathogenic missense variants in proofreading domains. Therefore, this criterion is not applied at Not Applied strength because missense is a known mechanism of disease.
BP2
BP2 (Not Applied) Strength Modified
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 or cis/trans data. Therefore, this criterion is not applied at Not Applied strength because variant phase information is lacking.
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, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because it does not involve an in-frame indel.
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: in silico predictors (CADD, PolyPhen-2, REVEL 0.22) and SpliceAI (0.03) predict no damaging effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect.
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 shows: no clinical case reports indicating alternative diagnoses. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
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'. The evidence for this variant shows: not reported as benign in any reputable database. Therefore, this criterion is not applied at Not Applied strength because no benign assertion exists.
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: it is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.