POLE c.846C>T, p.Pro282=
NM_006231.4:c.846C>T
Likely Benign
This synonymous POLE variant (c.846C>T, P282=) is present at low frequency in population cohorts, shows no computational or splicing impact, and is reported as benign by reputable sources; therefore it is classified as Likely Benign.
ACMG/AMP Criteria Applied
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.846C>T
Protein Change
P282=
Location
Exon 9
(Exon 9 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.846C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.104%
Common
Highest in Population
African/African American
1.11%
Common
Global: 0.104%
African/African American: 1.11%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282812Alt: 293Homozygotes: 2
ACMG Criteria Applied
None
This variant is present in gnomAD (MAF= 0.104%, 293/282812 alleles, homozygotes = 2) and at a higher frequency in the African/African American population (MAF= 1.11%, 276/24956 alleles, homozygotes = 2). The variant frequency does not support application of PM2, BA1, or BS1 criteria.
Classification
Likely Benign
Based on 15 submitter reviews in ClinVar
Submitter Breakdown
4 LB
11 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as Likely benign (4 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: 0.68
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 is a known mechanism of disease". The evidence for this variant shows: it is a synonymous change (P282=) with no impact on splicing. 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 for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: it is a synonymous change with no amino acid alteration. Therefore, this criterion is not applied because there is no 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: there is no data on de novo status. Therefore, this criterion is not applied due to lack of de novo information.
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 functional data are not available.
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 prevalence data in affected individuals. Therefore, this criterion is not applied due to missing case-control evidence.
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: no known hot spot or functional domain involvement. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
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: present in gnomAD at MAF=0.104% globally and 1.11% in African/African American. Therefore, this criterion is not applied because the variant is not absent or at extremely low frequency.
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 trans or phase information with a pathogenic variant. Therefore, this criterion is not applied due to missing phasing data.
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: it is a synonymous change with no protein length alteration. 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". The evidence for this variant shows: it is synonymous, not a missense change. 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, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption data. 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". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied due to lack of family segregation information.
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 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". The evidence for this variant shows: computational predictors (CADD=0.68, SpliceAI=0) support no deleterious effect. Therefore, this criterion is not applied because evidence supports benign impact.
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. 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". The evidence for this variant shows: no pathogenic assertions in reputable sources. 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 (stand-alone)". The evidence for this variant shows: MAF=0.104% globally and 1.11% in African/African American, below typical BA1 thresholds. 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 evidence for this variant shows: frequency does not clearly exceed disease expectations per pipeline summary. 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". The evidence for this variant shows: presence in gnomAD including homozygotes but health status unknown. 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". 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, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family data. 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 loss of function causes disease". The evidence for this variant shows: it is synonymous, not missense. 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". The evidence for this variant shows: no phase or cis/trans data. 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". The evidence for this variant shows: not an indel. 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". The evidence for this variant shows: CADD score 0.68 and SpliceAI scores 0, indicating no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational predictions support 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 etiologies. 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". The evidence for this variant shows: ClinVar entries include 11 Benign and 4 Likely Benign submissions. Therefore, this criterion is applied at Supporting strength because reputable sources assert benign classification without primary evidence available.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is synonymous (P282=) and SpliceAI predicts no splice impact. Therefore, this criterion is applied at Supporting strength because it meets the synonymous non-impact criterion.