POLE c.424-20G>A, p.?
NM_006231.4:c.424-20G>A
Likely Benign
NM_006231.4:c.424-20G>A in POLE is classified as Likely Benign based on Moderate evidence of extreme rarity in population databases (PM2) and multiple Supporting benign criteria (BP4, BP6). Computational predictions and lack of functional or segregation data further support a benign interpretation.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
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.424-20G>A
Protein Change
?
Location
Exon 5
(Exon 5 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.424-20G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0008%
Very Rare
Highest in Population
European (non-Finnish)
0.00177%
Rare
Global: 0.0008%
European (non-Finnish): 0.00177%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249862Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0008%, 2/249862 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00177%, 2/112832 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.18
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 (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 shows: c.424-20G>A is an intronic change outside of canonical splice sites and is not predicted to result in a null effect. Therefore, this criterion is not applied because the variant does not meet the definition of a null LoF variant.
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 known amino acid change or matching pathogenic variant. Therefore, this criterion is not applied because there is no evidence of a shared pathogenic 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 data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
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 there is no functional data supporting a damaging effect.
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 segregation data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied because there is no statistical evidence of enrichment in cases.
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: c.424-20G>A lies outside known functional domains and mutational hotspots. Therefore, this criterion is not applied because the variant is not located in a critical domain or hotspot.
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: gnomAD reports MAF=0.0008% (2/249862 alleles) with no homozygotes, indicating extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
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 allele. Therefore, this criterion is not applied because the variant has not been observed in trans with a pathogenic variant.
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: c.424-20G>A does not alter protein length. Therefore, this criterion is not applied because there is no impact on 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: variant is intronic with no amino acid change. Therefore, this criterion is not applied because it does not involve a missense alteration.
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 available. Therefore, this criterion is not applied due to lack of de novo evidence.
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 family studies are not available.
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: it is intronic, not missense. Therefore, this criterion is not applied because it is not a missense change.
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 predict no impact (SpliceAI=0.01, CADD=-0.18). 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 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 phenotypic specificity.
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: no reputable source reports it as pathogenic. Therefore, this criterion is not applied because there is no conflicting pathogenic report.
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=0.0008%, below any BA1 threshold. Therefore, this criterion is not applied because the allele frequency is not too high.
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: MAF=0.0008%, below expected maximum for POLE-related conditions. Therefore, this criterion is not applied because frequency does not exceed expectations.
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: observed in gnomAD but disease penetrance and age of onset for POLE-associated conditions may vary. Therefore, this criterion is not applied due to uncertainty about penetrance and age.
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 available. 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 family segregation data. Therefore, this criterion is not applied because 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 LoF causes disease". The evidence for this variant shows: it is intronic and not missense. Therefore, this criterion is not applied because it is not a missense change.
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 cis/trans configuration with pathogenic alleles. Therefore, this criterion is not applied due to lack of evidence.
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 single nucleotide change and not an indel. Therefore, this criterion is not applied because it 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 (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: SpliceAI score 0.01 and CADD score -0.18 indicate no predicted impact on splicing or function. Therefore, this criterion is applied at Supporting strength because computational evidence supports 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 shows: no case reports with alternate diagnoses. Therefore, this criterion is not applied because there is no such case context.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: ClinVar entries from three clinical laboratories list it as Likely benign without accessible primary data. Therefore, this criterion is applied at Supporting strength because a reputable source reports benign classification without primary evidence.
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: c.424-20G>A is intronic, not synonymous. Therefore, this criterion is not applied because it does not meet the definition of a synonymous silent change.