About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.1687-18G>A, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Met
PM2
The variant is rare in population databases: gnomAD v4.1 total AF is 5.52852e-06 (0.00055%) with highest population AF 4.65398e-05 (0.00465%), and gnomAD v2.1 total AF is 1.19404e-05 (0.00119%) with highest population AF 3.26627e-05 (0.00327%); these values are below the non-VCEP PM2 threshold of 0.1%.
Benign criteria applied · 1
BP4Met
BP4
SpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to flag splice-impact concern, supporting a benign computational assessment.
Recorded classification: Uncertain significance
generic_acmg_2015_with_non_vcep_frequency_thresholds
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,447,042 alleles
gnomAD v4.1: 8 / 1,447,042 alleles. Recorded AF 5.52852e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19404e-05; MAF= 0.00119%, 3/251248 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006231.4:c.1687-18G>A is a noncanonical intronic POLE variant observed in gnomAD v4.1 at 8/1447042 alleles (AF 5.52852e-06; 0.00055%), with the highest frequency in South Asians at 4/85948 alleles (AF 4.65398e-05; 0.00465%), which is below the non-VCEP PM2 threshold of 0.1%.
Population data are similarly rare in gnomAD v2.1 at 3/251248 alleles (AF 1.19404e-05; 0.00119%), with the highest South Asian frequency at 1/30616 alleles (AF 3.26627e-05; 0.00327%), and these values also remain below the BS1 threshold of 0.3% and BA1 threshold of 1%.
SpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to indicate splice-impact concern and supports a benign computational assessment under BP4 rather than pathogenic computational evidence.
ClinVar contains a single submitter classification of Likely benign, which is directionally consistent with the splice prediction but is not used here as a standalone ACMG criterion.
With conflicting supporting evidence from rarity and benign computational data, and without stronger pathogenic or benign evidence, NM_006231.4:c.1687-18G>A is classified as a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 MetThe variant is rare in population databases: gnomAD v4.1 total AF is 5.52852e-06 (0.00055%) with highest population AF 4.65398e-05 (0.00465%), and gnomAD v2.1 total AF is 1.19404e-05 (0.00119%) with highest population AF 3.26627e-05 (0.00327%); these values are below the non-VCEP PM2 threshold of 0.1%. Details ▾Hide ▴
Rule
Non-VCEP default frequency threshold used here: PM2 if AF < 0.1%.
Evidence considered
- gnomAD v4.1: 8/1447042 alleles, total AF 5.528519559211136e-06, best subpopulation South Asian AF 4.65397682319542e-05.
- gnomAD v2.1: 3/251248 alleles, total AF 1.1940393555371585e-05, best subpopulation South Asian AF 3.266266004703423e-05.
Still missing
- No disease-specific allele-frequency threshold for POLE was provided.
Sources
BP4 MetSpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to flag splice-impact concern, supporting a benign computational assessment. Details ▾Hide ▴
Rule
BP4 applies when multiple computational methods suggest no impact on gene or gene product.
Evidence considered
- DS_AG 0.0, DS_AL 0.01, DS_DG 0.01, DS_DL 0.0; max delta score 0.01.
Still missing
- No RNA study was provided, although current computational evidence argues against splice disruption.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This is a noncanonical intronic variant at c.1687-18, and SpliceAI predicts a maximum delta score of 0.01 rather than a loss-of-function splice effect. Details ▾Hide ▴
Rule
PVS1 requires a predicted or proven null variant in a gene where loss of function is a known disease mechanism.
Evidence considered
- Variant position is intronic and outside the canonical splice dinucleotide.
- SpliceAI max delta score = 0.01.
Still missing
- No RNA study was provided to demonstrate aberrant splicing.
Sources
PP3 Computational evidence does not support a deleterious splice effect because SpliceAI shows a maximum delta score of 0.01. Details ▾Hide ▴
Rule
PP3 applies when multiple computational methods support a deleterious effect.
Evidence considered
- SpliceAI max delta score = 0.01.
Still missing
- Additional splice predictors could be reviewed if needed, although current data do not suggest splice disruption.
Sources
PP5 No reputable-source pathogenic classification was provided for this variant. Details ▾Hide ▴
Rule
PP5 applies when a reputable source reports a variant as pathogenic without available evidence.
Evidence considered
- ClinVar classification is Likely benign from a single submitter.
Sources
clinvar ↗28492532
BA1 The highest observed population frequency is 4.65398e-05 (0.00465%) in gnomAD v4.1 South Asians, which is below the non-VCEP BA1 threshold of 1%. Details ▾Hide ▴
Rule
Non-VCEP default frequency threshold used here: BA1 if AF > 1%.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 4.65397682319542e-05.
Sources
BS1 The highest observed population frequency is 4.65398e-05 (0.00465%) in gnomAD v4.1 South Asians, which is below the non-VCEP BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
Non-VCEP default frequency threshold used here: BS1 if AF > 0.3%.
Evidence considered
- gnomAD v4.1 best subpopulation AF = 4.65397682319542e-05.
Sources
Not assessed · 13 · no assessment recorded
PS2 No de novo data were provided. Details ▾Hide ▴
Rule
PS2 applies to a confirmed de novo pathogenic variant.
Still missing
- Confirmed maternity and paternity data.
PS3 No well-established functional assay data were provided for this variant. Details ▾Hide ▴
Rule
PS3 applies when well-established functional studies support a damaging effect.
Still missing
- Validated functional or RNA assay data.
PS4 No case-control enrichment or multiple affected observations were provided. Details ▾Hide ▴
Rule
PS4 applies when prevalence in affected individuals is significantly increased over controls.
Still missing
- Published case series or case-control data.
PM6 No assumed de novo data were provided. Details ▾Hide ▴
Rule
PM6 applies to an assumed de novo variant without full confirmation.
Still missing
- Parental testing information.
PP1 No segregation data were provided. Details ▾Hide ▴
Rule
PP1 applies when a variant cosegregates with disease in multiple affected family members.
Still missing
- Family segregation studies.
PP4 No phenotype or family history data specific to a POLE-associated syndrome were provided. Details ▾Hide ▴
Rule
PP4 applies when the phenotype or family history is highly specific for a disease with a single genetic etiology.
Still missing
- Detailed personal and family cancer phenotype.
BS2 No evidence was provided showing the variant in healthy adults in a context sufficient to satisfy BS2. Details ▾Hide ▴
Rule
BS2 applies when a variant is observed in healthy adults for a fully penetrant dominant or expected-age-onset disorder.
Evidence considered
- No homozygotes were observed in gnomAD.
Still missing
- Phenotyped unaffected carrier data.
BS3 No well-established functional studies demonstrating lack of damaging effect were provided. Details ▾Hide ▴
Rule
BS3 applies when well-established functional studies show no damaging effect.
Still missing
- Validated benign functional or RNA assay data.
BS4 No segregation data demonstrating lack of cosegregation were provided. Details ▾Hide ▴
Rule
BS4 applies when a variant does not segregate with disease.
Still missing
- Pedigree segregation data.
BP2 No phase data with another pathogenic variant were provided. Details ▾Hide ▴
Rule
BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder or in cis for any inheritance pattern.
Still missing
- Phase information.
BP5 No alternate molecular explanation for the phenotype was provided. Details ▾Hide ▴
Rule
BP5 applies when a variant is found in a case with an alternate molecular basis for disease.
Still missing
- Comprehensive phenotype and other molecular findings.
BP6 ClinVar contains a single Likely benign submission, but the available record does not by itself establish BP6 as a standalone criterion in this review. Details ▾Hide ▴
Rule
BP6 applies when a reputable source reports a variant as benign without available evidence.
Evidence considered
- ClinVar classification: Likely benign, criteria provided, single submitter.
Still missing
- Independent benign classification from a clearly established reputable source, if BP6 is to be used.
Sources
clinvar ↗28492532
BP7 The variant is intronic and outside the canonical splice site with a low SpliceAI score, but no additional conservation assessment or specification allowing BP7 use in this context was provided. Details ▾Hide ▴
Rule
BP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation.
Evidence considered
- Variant position c.1687-18.
- SpliceAI max delta score = 0.01.
Still missing
- Conservation data or an explicit specification extending BP7 to this intronic position.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this variant does not define an amino acid substitution. Details ▾Hide ▴
Rule
PS1 applies to the same amino acid change as a known pathogenic variant.
Evidence considered
- Predicted protein consequence is p.?.
PM1 N/APM1 is not applicable because this is not a missense or in-frame coding change localizable to a mutational hot spot or critical protein domain. Details ▾Hide ▴
Rule
PM1 applies to variants in a mutational hot spot or critical functional domain without benign variation.
Evidence considered
- Variant is intronic.
PM3 N/APM3 is not applicable because this criterion is intended for recessive disorders and no trans configuration evidence was provided. Details ▾Hide ▴
Rule
PM3 applies to recessive disorders with variants detected in trans.
PM4 N/APM4 is not applicable because this variant is not an in-frame deletion, insertion, or stop-loss event. Details ▾Hide ▴
Rule
PM4 applies to protein length changes due to in-frame indels or stop-loss variants.
Evidence considered
- Variant is intronic.
PM5 N/APM5 is not applicable because this variant does not encode a missense change. Details ▾Hide ▴
Rule
PM5 applies to a novel missense change at a residue where a different pathogenic missense change has been seen.
Evidence considered
- Predicted protein consequence is p.?.
PP2 N/APP2 is not applicable because this is not a missense variant. Details ▾Hide ▴
Rule
PP2 applies to missense variants in genes with low benign missense variation and common pathogenic missense mechanism.
Evidence considered
- Variant is intronic.
BP1 N/ABP1 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Rule
BP1 applies to missense variants in genes where truncating variants are primarily pathogenic.
Evidence considered
- Variant is intronic.
BP3 N/ABP3 is not applicable because this is not an in-frame indel or repeat-region event. Details ▾Hide ▴
Rule
BP3 applies to in-frame deletions or insertions in repetitive regions without known function.
Evidence considered
- Variant is intronic.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.1687-18G>A
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132672340 C>T
- GRCh37
- chr12:133248926 C>T
Gene diagram
Every interpreted variant in POLE, mapped onto the exon structure of NM_006231.4. Select a row to find it on the plot.
POLENM_006231.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLE
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
8 / 1,447,042 alleles
AF 5.53e-06 · 0 homozygotes · FAF 1.59e-05
gnomAD v2.1
3 / 251,248 alleles
AF 1.19e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 5.5e-06 · 8 / 1,447,042 alleles · 0 hom · FAF 1.6e-05
| South Asian4 / 85,948 | 4.7e-05 |
| East Asian1 / 39,638 | 2.5e-05 |
| Admixed American1 / 44,706 | 2.2e-05 |
| European (non-Finnish)2 / 1,098,652 | 1.8e-06 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, European (Finnish), Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,248 alleles · 0 hom
| South Asian1 / 30,616 | 3.3e-05 |
| Admixed American1 / 34,580 | 2.9e-05 |
| European (non-Finnish)1 / 113,702 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.52852e-06; MAF= 0.00055%, 8/1447042 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.65398e-05; MAF= 0.00465%, 4/85948 alleles, homozygotes = 0); grpmax FAF= 1.586e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19404e-05; MAF= 0.00119%, 3/251248 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 MetSpliceAI predicts a maximum delta score of 0.01, which is below the 0.2 threshold commonly used to flag splice-impact concern, supporting a benign computational assessment. Details ▾Hide ▴
Rule
BP4 applies when multiple computational methods suggest no impact on gene or gene product.
Evidence considered
- DS_AG 0.0, DS_AL 0.01, DS_DG 0.01, DS_DL 0.0; max delta score 0.01.
Still missing
- No RNA study was provided, although current computational evidence argues against splice disruption.
Sources
PP3 Computational evidence does not support a deleterious splice effect because SpliceAI shows a maximum delta score of 0.01. Details ▾Hide ▴
Rule
PP3 applies when multiple computational methods support a deleterious effect.
Evidence considered
- SpliceAI max delta score = 0.01.
Still missing
- Additional splice predictors could be reviewed if needed, although current data do not suggest splice disruption.
Sources
BP7 The variant is intronic and outside the canonical splice site with a low SpliceAI score, but no additional conservation assessment or specification allowing BP7 use in this context was provided. Details ▾Hide ▴
Rule
BP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation.
Evidence considered
- Variant position c.1687-18.
- SpliceAI max delta score = 0.01.
Still missing
- Conservation data or an explicit specification extending BP7 to this intronic position.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,447,042 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1630686/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133248926-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132672340-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.1687…
- OncoKB ↗www.oncokb.org/gene/POLE
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.52852e-06; MAF= 0.00055%, 8/1447042 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.65398e-05; MAF= 0.00465%, 4/85948 alleles, homozygotes = 0); grpmax FAF= 1.586e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19404e-05; MAF= 0.00119%, 3/251248 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).