POLE c.3275+10C>T, p.?
NM_006231.4:c.3275+10C>T
Likely Benign
This intronic POLE variant at +10 is extremely rare (PM2) and computational/splice predictions are benign (BP4), with a ClinVar report of Likely benign (BP6). However, the moderate PM2 pathogenic evidence conflicts with two supporting benign criteria, resulting in an overall classification of VUS.
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.3275+10C>T
Protein Change
?
Location
Exon 26
(Exon 26 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.3275+10C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000404%
Extremely Rare
Highest in Population
South Asian
0.00328%
Rare
Global: 0.000404%
South Asian: 0.00328%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 247828Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000404%, 1/247828 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00328%, 1/30524 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: 0.31
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 – Null variant in a gene where loss of function is a known mechanism of disease. The evidence for this variant shows: it is an intronic change at position +10 outside the canonical splice site, not predicted to create a null allele. Therefore, this criterion is not applied because the variant is not a null variant or canonical ±1/2 splice site change.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change. The evidence for this variant shows: it is intronic and does not alter an amino acid. Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. The evidence for this variant shows: no parental testing or de novo data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product. The evidence for this variant shows: no functional assays have been performed. Therefore, this criterion is not applied because functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 – Prevalence in affected individuals significantly increased compared with controls. The evidence for this variant shows: no case-control or familial segregation data. Therefore, this criterion is not applied due to lack of prevalence evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 – Located in a mutational hot spot or well-established functional domain without benign variation. The evidence for this variant shows: it is in an intronic region outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, PM2 – Absent from controls (or at extremely low frequency if recessive). The evidence for this variant shows: MAF=0.000404% in gnomAD (1/247,828 alleles), extremely rare. 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, PM3 – Detected in trans with a pathogenic variant (for recessive disorders). The evidence for this variant shows: no trans-phase data with a pathogenic allele. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants. The evidence for this variant shows: no change in protein length (intronic). Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen. The evidence for this variant shows: it is intronic, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 – Assumed de novo, but without confirmation of paternity and maternity. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 – Co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 – 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.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product. The evidence for this variant shows: CADD score 0.31 and SpliceAI scores 0.00 predict no impact. 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, PP4 – 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 provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 – 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.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 – Allele frequency is too high for the disorder. The evidence for this variant shows: MAF 0.000404%, which is below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 – Allele frequency is greater than expected for the disorder. The evidence for this variant shows: MAF 0.000404%, not greater than expected. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 – Observed in healthy individuals with full penetrance expected at an early age. The evidence for this variant shows: population data does not confirm health status or penetrance. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 – 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.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 – Lack of segregation in affected family members. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 – Missense variant in a gene where only loss-of-function causes disease. The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 – In-frame deletions/insertions in a repetitive region without known function. The evidence for this variant shows: it is a single-nucleotide change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product. The evidence for this variant shows: CADD score 0.31 and SpliceAI scores 0.00 predict no effect 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, BP5 – Variant found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no case reports with alternate etiology. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 – Reputable source reports variant as benign, but without accessible evidence. The evidence for this variant shows: ClinVar entry reports Likely benign (1 submitter) without detailed evidence. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 – Synonymous variant with no predicted impact on splicing. The evidence for this variant shows: it is intronic, not synonymous. Therefore, this criterion is not applied.