POLE c.3490C>T, p.Pro1164Ser
NM_006231.4:c.3490C>T
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.598
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.3490C>T
Protein Change
P1164S
Location
Exon 29
(Exon 29 of 49)
5'
Exon Structure (49 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1164 in gene POLE
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 1 submitter review 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 (1 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
No evidence of other pathogenic variants at position 1164 in gene POLE
Functional Studies
Summary
The POLE P1164S variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.598
0.598
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
Benign:
CADD: 5.16
metasvm: T
metalr: T
primateai: T
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 (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant indicates it is a missense change (P1164S) and is not expected to result in loss of function. Therefore, this criterion is not applied because the variant does not represent 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 indicate that the same amino acid change has been observed as pathogenic. Therefore, this criterion is not applied.
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'. There is no evidence provided regarding a confirmed de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines, the finding for PS3 is: 'The POLE P1164S variant has not been functionally characterized, and its biological significance remains unknown'. The evidence shows that there are no well-established functional studies supporting a damaging effect. Therefore, this criterion is not applied.
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'. There is no evidence provided of increased prevalence in affected individuals for this variant. Therefore, this criterion is not applied.
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'. There is no evidence indicating that the variant is located in a recognized mutational hot spot or critical functional domain. Therefore, this criterion is not applied.
PM2
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 shows that the variant is not found in population databases (gnomAD reports a MAF of 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from controls.
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)'. There is no evidence provided that this variant is in trans with a pathogenic variant. Therefore, this criterion is not applied.
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 variant under consideration is a missense change and does not cause a protein length change. Therefore, this criterion is not applied.
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'. There is no evidence that a different pathogenic missense change at codon 1164 has been documented. Therefore, this criterion is not applied.
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'. There is no information suggesting a de novo occurrence for this variant. Therefore, this criterion is not applied.
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'. There is no segregation data provided for this variant. Therefore, this criterion is not applied.
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'. There is insufficient evidence regarding the specific missense constraint for POLE in this context. Therefore, this criterion is not applied.
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 or gene product'. The evidence for this variant is mixed: while PolyPhen predicts a 'probably damaging' effect, other predictors (including CADD, MetaSVM, MetaLR, and PrimateAI) as well as SpliceAI (which shows no impact on splicing) suggest a benign impact. Because the overall computational evidence does not conclusively support a deleterious effect, this criterion is not applied.
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'. There is no clinical phenotype information provided that is specific to a disease known to be caused solely by variants in POLE. Therefore, this criterion is not applied.
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 variant is reported in ClinVar as VUS and not as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (typically >5%)'. The variant is absent from controls, with a frequency of 0%. Therefore, this criterion is not applied.
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'. Since the variant is absent from population databases, this criterion is not met and therefore not applied.
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'. There is no evidence indicating that this variant has been observed in healthy individuals. Therefore, this criterion is not applied.
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'. Although SpliceAI analysis shows no predicted impact on splicing, there are no comprehensive functional studies demonstrating lack of damage. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. There is no segregation analysis available for this variant, thus this criterion is not applied.
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'. There is no specific evidence to indicate that only loss-of-function mutations in POLE cause disease. Therefore, this criterion is not applied.
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'. There is no evidence that this variant occurs in trans or in cis with any pathogenic variant. Therefore, this criterion is not applied.
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 variant is a missense change and does not represent an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
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 (e.g., conservation, evolutionary, splicing impact)'. The evidence shows that while one predictor (PolyPhen) suggests a probably damaging effect, the majority of other in silico tools (including CADD, MetaSVM, MetaLR, and PrimateAI) support a benign interpretation, and SpliceAI indicates no splicing impact. Therefore, this criterion is applied at Supporting strength because the overall computational evidence favors 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'. There is no evidence suggesting an alternate molecular cause in the cases where this variant was identified. Therefore, this criterion is not applied.
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 reported this variant as VUS rather than benign, there is no reputable source asserting it as benign without evidence. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. Since the variant results in a missense change and is not synonymous, this criterion is not applicable and therefore not applied.