POLE c.3594C>T, p.Ala1198=
NM_006231.4:c.3594C>T
Likely Benign
This synonymous POLE variant (c.3594C>T; A1198=) is classified as Likely Benign based on moderate evidence of rarity (PM2) and multiple supporting benign criteria (BP4, BP6, BP7). There is no evidence supporting a damaging effect or association with disease.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.3594C>T
Protein Change
A1198=
Location
Exon 30
(Exon 30 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
Loading genome browser...
HGVS InputNM_006231:c.3594C>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.00678%
Rare
Highest in Population
Admixed American
0.0376%
Low Frequency
Global: 0.00678%
Admixed American: 0.0376%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250558Alt: 17Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00678%, 17/250558 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.0376%, 13/34542 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 LB
1 B
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) and as Benign (1 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: 0.28
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'. The evidence for this variant shows a synonymous change (A1198=) with no impact on protein coding. Therefore, this criterion is not applied.
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 amino acid change (synonymous). 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 are no de novo data available. Therefore, this criterion is not applied.
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'. No functional studies are available for this variant. 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 significantly increased compared with controls'. No case–control or disease‐specific prevalence data are available. 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'. This variant is not located in a known functional domain or hot spot. 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)'. The evidence for this variant shows a MAF of 0.00678% in gnomAD, below the 0.1% threshold. Therefore, this criterion is applied at Moderate strength because the variant is 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'. Zygosity and trans‐phase data are not available. 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'. This is a synonymous substitution with no 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'. This variant is synonymous, not missense. 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, without confirmation of paternity and maternity'. No de novo or parental data are available. 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'. No segregation data are available. 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'. This variant is synonymous, not missense. 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/gene product'. Computational tools (CADD=0.28, SpliceAI=0) predict no deleterious effect. Therefore, 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 highly specific for a disease with a single genetic etiology'. No phenotype or clinical context is provided. 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'. Reputable sources report this variant as benign. 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'. The allele frequency (0.00678%) is well below any BA1 threshold. 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'. The allele frequency is very low and not greater than expected. Therefore, this criterion is not applied.
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'. No specific healthy‐individual penetrance data are available. 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'. No functional studies are available. 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'. No family segregation data are available. Therefore, 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 where only LoF causes disease'. This variant is synonymous. 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'. No such data are available. 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'. Not applicable to this synonymous substitution. 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'. Computational tools report CADD=0.28 and SpliceAI=0 (no splice impact). Therefore, this criterion is applied at Supporting strength because in silico evidence indicates no deleterious 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'. No such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. ClinVar reports this variant as Likely Benign (3 labs) and Benign (1 lab). Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. This is a synonymous A1198= change and SpliceAI scores are 0, indicating no splicing effect. Therefore, this criterion is applied at Supporting strength.