POLE c.6748-28G>T, p.?
NM_006231.4:c.6748-28G>T
Likely Benign
The intronic POLE variant c.6748-28G>T is extremely rare (PM2), predicted benign by computational tools (BP4), and reported likely benign in ClinVar (BP6). No other pathogenic evidence is present. The combined evidence supports a Likely Benign classification.
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.6748-28G>T
Protein Change
?
Location
Exon 48
(Exon 48 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.6748-28G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0207%
Low Frequency
Highest in Population
European (non-Finnish)
0.0353%
Low Frequency
Global: 0.0207%
European (non-Finnish): 0.0353%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 280250Alt: 58Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0207%, 58/280250 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0353%, 45/127502 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 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 (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: 0.03
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 exon deletion in a LoF gene)". The evidence for this variant shows: c.6748-28G>T is an intronic change outside the canonical ±1 or 2 splice sites and is not predicted to cause a null effect. Therefore, this criterion is not applied at Not Applied because the variant does not meet the requirements for 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 known pathogenic variant but different nucleotide change". The evidence for this variant shows: no amino acid change is predicted or reported. Therefore, this criterion is not applied at Not Applied because there is no established pathogenic 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 information on de novo status or parental genotypes. Therefore, this criterion is not applied at Not Applied because de novo confirmation data are lacking.
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 have been performed for POLE c.6748-28G>T. Therefore, this criterion is not applied at Not Applied because functional data are not available.
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-population data. Therefore, this criterion is not applied at Not Applied due to absence of prevalence data.
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: the intronic position c.6748-28G>T is not in a known functional domain or hotspot. Therefore, this criterion is not applied at Not Applied because the variant location is not within a recognized hotspot or critical domain.
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: MAF=0.0207% in gnomAD (58/280250 alleles, no homozygotes), consistent with extreme rarity. Therefore, this criterion is applied at Moderate strength because the variant is absent or at 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: no data on phase or presence of another pathogenic allele. Therefore, this criterion is not applied at Not Applied due to lack of trans configuration data.
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: c.6748-28G>T does not alter protein length (intronic). Therefore, this criterion is not applied at 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 amino acid change is involved. Therefore, this criterion is not applied at Not Applied because PM5 is not relevant.
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 or parental data. Therefore, this criterion is not applied at Not Applied due to lack of de novo evidence.
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 segregation data. Therefore, this criterion is not applied at Not Applied because family 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: it is intronic, not missense. Therefore, this criterion is not applied at Not Applied because PP2 is not relevant to intronic variants.
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/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico tools (SpliceAI, CADD) predict no impact or benign effect. Therefore, this criterion is not applied at 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 clinical phenotype or family history data are provided. Therefore, this criterion is not applied at Not Applied due to absence of phenotype information.
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: no reputable source reports pathogenicity. Therefore, this criterion is not applied at Not Applied because PP5 is not triggered.
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 (based on population data)". The evidence for this variant shows: MAF=0.0207%, which is below typical BA1 thresholds. Therefore, this criterion is not applied at Not Applied because the allele frequency is not above disease-specific thresholds.
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=0.0207%, which does not exceed expected thresholds for POLE-related disorders. Therefore, this criterion is not applied at Not Applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no clinical assessment of gnomAD carriers. Therefore, this criterion is not applied at Not Applied due to lack of confirmed healthy carrier evaluations.
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 studies available. Therefore, this criterion is not applied at Not Applied because no functional evidence exists to support BS3.
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 in families. Therefore, this criterion is not applied at Not Applied due to absence of familial data.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: intronic location, not missense. Therefore, this criterion is not applied at Not Applied because BP1 does not apply.
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 phase information or co-occurrence data. Therefore, this criterion is not applied at Not Applied because BP2 conditions are unmet.
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: single nucleotide change in intron, not an in-frame indel. Therefore, this criterion is not applied at Not Applied because it is not relevant.
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 (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: SpliceAI predicts no impact (max score 0.01), CADD=0.03. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict no deleterious 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 case reports with alternate molecular diagnoses. Therefore, this criterion is not applied at Not Applied.
BP6
BP6 (Supporting)
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: ClinVar entry from a clinical laboratory classifies it as Likely benign. Therefore, this criterion is applied at Supporting strength because a reputable source reports benign status without underlying accessible data.
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: intronic change, not synonymous coding. Therefore, this criterion is not applied at Not Applied because BP7 is limited to synonymous variants.