POLE c.449G>A, p.Arg150Gln
NM_006231.4:c.449G>A
COSMIC ID: COSM8891164
Variant of Uncertain Significance (VUS)
Based on the extremely low population frequency (PM2 Moderate) and multiple computational predictions indicating no impact (BP4 Supporting), and in the absence of additional supporting evidence, the variant 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.449G>A
Protein Change
R150Q
Location
Exon 6
(Exon 6 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 150 in gene POLE
Alternate Identifiers
COSM8891164
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.449G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00239%
Rare
Highest in Population
South Asian
0.00653%
Rare
Global: 0.00239%
South Asian: 0.00653%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251146Alt: 6Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00239%, 6/251146 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00653%, 2/30610 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
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 150 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.299
0.299
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: 3.75polyphen_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/finding 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 or multi-exon deletion in a LoF gene)'. The evidence for this variant shows: It is a missense variant (p.R150Q), not a null 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/finding for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: No known pathogenic variant at amino acid position 150 in POLE. Therefore, this criterion is not applied because there is no established pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 data. Therefore, this criterion is not applied because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 available. Therefore, this criterion is not applied because functional impact has not been experimentally characterized.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: No case-control or affected individual data. Therefore, this criterion is not applied because no prevalence data in affected individuals is available.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: p.R150Q lies outside the POLE exonuclease domain where pathogenic missense variants cluster. Therefore, this criterion is not applied because the variant is not located in a known functional domain hot spot.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule/finding for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: gnomAD MAF = 0.00239%, present in 6/251,146 alleles, extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is present at an extremely low frequency in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: POLE-associated disease is autosomal dominant and no trans observations are relevant. Therefore, this criterion is not applied because it is not relevant for a dominant disorder.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 missense change with no alteration in protein length. Therefore, this criterion is not applied because there is no change in protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 150. Therefore, this criterion is not applied because there is no precedent of pathogenic variation at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: No de novo data available. Therefore, this criterion is not applied because assumed de novo status cannot be assigned.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 because segregation information is not available.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 disease mechanism is primarily missense in the exonuclease domain; R150Q lies outside that domain. Therefore, this criterion is not applied because the variant context does not meet the gene-specific missense mechanism.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 predictors (CADD, PolyPhen, REVEL=0.30) predict benign impact and SpliceAI=0.02 indicates no splicing 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/finding 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 patient phenotype or family history data provided. Therefore, this criterion is not applied because phenotype specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: ClinVar reports as Uncertain Significance. Therefore, this criterion is not applied because no reputable source classifies it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: MAF=0.00239%, below common benign thresholds. Therefore, this criterion is not applied because the allele frequency is not above the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF is very low and not greater than expected. Therefore, this criterion is not applied because the allele frequency does not exceed expected disease thresholds.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: 'Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: No reports of observation in healthy adults. Therefore, this criterion is not applied because healthy individual data are not available.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: No functional study data. Therefore, this criterion is not applied because functional data are missing.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 familial segregation information is unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease'. The evidence for this variant shows: POLE-associated disease is driven by specific missense variants in the exonuclease domain. Therefore, this criterion is not applied because missense is a known disease mechanism in POLE.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 cis or trans observations. Therefore, this criterion is not applied because phasing information is not available.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: It is a missense change, not an in-frame indel. Therefore, this criterion is not applied because the variant type does not match.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule/finding 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, REVEL=0.30) predict benign impact and SpliceAI=0.02 indicates no splicing effect. Therefore, this criterion is applied at Supporting strength because computational evidence consistently supports a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: No such case data. Therefore, this criterion is not applied because no alternate molecular basis has been reported.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: No reputable source classifies it as benign. Therefore, this criterion is not applied because no such report exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 because the variant is not synonymous.