POLE c.1807A>G, p.Ile603Val
NM_006231.4:c.1807A>G
Variant of Uncertain Significance (VUS)
Variant NM_006231.4:c.1807A>G (p.I603V) in POLE is absent from population databases (PM2) and has benign computational predictions (BP4). No additional pathogenic or benign evidence is available, resulting in a classification of Variant of Uncertain Significance (VUS).
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.1807A>G
Protein Change
I603V
Location
Exon 17
(Exon 17 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 603 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.1807A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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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 603 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.16
0.16
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: 2.68polyphen_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 in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: I603V is a missense variant, not a null (nonsense, frameshift, canonical splice site) variant. Therefore, this criterion is not applied because the variant is not a null variant.
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 shows: no previously established pathogenic variant at codon 603. Therefore, this criterion is not applied because there is no known pathogenic variant at the same residue.
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 data on de novo occurrence. Therefore, this criterion is not applied because de novo status has not been demonstrated.
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 because functional 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. Therefore, this criterion is not applied because no statistical evidence of enrichment in affected individuals is available.
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: residue I603 is not in a known mutational hotspot or characterized functional domain. Therefore, this criterion is not applied because the variant is not located in a defined 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: the variant is not found in population databases (gnomAD MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population 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.' The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied because trans occurrence has not been demonstrated.
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: I603V is a single amino acid substitution, not an in-frame indel or stop-loss. Therefore, this criterion is not applied because there is no protein length change.
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 change has been reported at residue 603. Therefore, this criterion is not applied because there is no known pathogenic variant at the same residue.
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 data or parental testing. Therefore, this criterion is not applied because de novo status is not established.
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 segregation data. Therefore, this criterion is not applied because there is no family segregation information.
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: insufficient data on POLE missense variation rates and disease mechanism frequency. Therefore, this criterion is not applied due to lack of evidence on gene-specific missense tolerance.
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 shows: in silico tools (CADD, PolyPhen, REVEL, SpliceAI) predict a benign effect. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
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 shows: no phenotype or family history data provided. Therefore, this criterion is not applied due to lack of phenotype information.
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 as pathogenic in ClinVar or other authoritative sources. Therefore, this criterion is not applied 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: MAF=0% in population databases. Therefore, this criterion is not applied because the variant frequency is not above the BA1 threshold.
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: absent from population databases. Therefore, this criterion is not applied because allele frequency is not greater than expected.
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 or X-linked disorder with full penetrance expected at an early age.' The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied because there is no healthy adult occurrence data.
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 studies. Therefore, this criterion is not applied because functional data are lacking.
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 segregation data. Therefore, this criterion is not applied because family segregation has not been assessed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease.' The evidence for this variant shows: POLE disease mechanism includes missense variants in the exonuclease domain. Therefore, this criterion is not applied because POLE pathogenicity can arise from missense changes.
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 data on phase with other variants. Therefore, this criterion is not applied because phase information is unavailable.
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: I603V is a single amino acid substitution, not an in-frame indel. Therefore, this criterion is not applied because the variant is not 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: CADD, PolyPhen, REVEL and SpliceAI predict a benign or no impact outcome. 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 case reports with alternative molecular findings. Therefore, this criterion is not applied because no such cases exist.
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 ClinVar or other sources. Therefore, this criterion is not applied because no such 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: I603V is a missense change, not synonymous. Therefore, this criterion is not applied because the variant is not synonymous.