About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.1367C>T, p.(Ala456Val)
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 León-Castillo et al. 2020 custom POLE framework. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the project's PM2 threshold of 0.1%.
PP3Supporting
PP3 · supporting
This variant is listed in León-Castillo Supplementary Table S3 as p.A456V with REVEL classified as likely disease causing and 0 benign in silico results, which meets the local POLE PP3 rule. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.10, supporting interpretation as a missense effect rather than a splice-disrupting variant.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
León-Castillo et al. 2020 custom POLE framework for criterion specification, using ACMG/AMP 2015 final classification combination thresholds as defined in the explicit final-classification framework.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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 ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 14 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The POLE c.1367C>T (p.Ala456Val) variant has been observed in somatic cancers in COSMIC (COSV57673561, n=2) and has not been reported in ClinVar.
The variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 that is below the project's PM2 threshold of 0.1%.
In León-Castillo Supplementary Table S3, p.Ala456Val is listed as likely disease causing with 0 benign in silico results, meeting the local POLE PP3 rule; SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the project's PM2 threshold of 0.1%. Details ▾Hide ▴
Rule
Generic population-frequency fallback using the project's PM2 threshold of <0.1%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PP3 SupportingThis variant is listed in León-Castillo Supplementary Table S3 as p.A456V with REVEL classified as likely disease causing and 0 benign in silico results, which meets the local POLE PP3 rule. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.10, supporting interpretation as a missense effect rather than a splice-disrupting variant. Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: PP3_Supporting when the exact variant is in Table S2 or S3, REVEL class is likely disease causing, and benign in silico results are <=1.
Evidence considered
- Supplementary Table S3: A456V, REVEL class 'likely disease causing', benign in silico results = 0.
- SpliceAI max delta score = 0.10.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4spliceai ↗
Not met · 7 · evaluated, threshold not reached
PS1 No established pathogenic variant causing the same amino acid change p.(Ala456Val) was identified, so PS1 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar has no entry for this variant.
Still missing
- No pathogenic classification for the exact same amino acid substitution was identified.
Sources
PS4 This variant has been reported in COSMIC 2 times, but the local POLE framework requires recurrence in both the COSMIC and TCGA endometrial carcinoma cohorts, a combined endometrial carcinoma count of at least 10, and membership in the established pathogenic set; these requirements are not met for p.(Ala456Val). Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: PS4_Supporting only for exact variants recurrent in both COSMIC and TCGA EC cohorts with combined count >=10 and in the established pathogenic set.
Evidence considered
- COSMIC COSV57673561 with somatic count 2.
- The custom POLE framework limits PS4_Supporting to exact recurrent variants present in both COSMIC and TCGA with combined EC count >=10 and in the established pathogenic set.
Still missing
- No TCGA endometrial carcinoma recurrence meeting the local PS4 rule was identified.
- The observed somatic count of 2 is below the required combined count threshold of 10.
Sources
cosmic ↗vcep_p_a_t_h___2_5_0___3_2_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2final_classification_framework
PM1 The local POLE framework does not allow PM1 based only on location in the exonuclease domain. p.(Ala456Val) is not one of the exact hotspot or recurrent substitutions specified for PM1, and the same codon shows heterogeneous substitutions including the hotspot p.(Ala456Pro), so PM1 is not met. Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: do not apply PM1 solely for exonuclease-domain location; use only exact framework-listed substitutions.
Evidence considered
- PM1_Strong in the local framework includes p.A456P but not p.A456V.
- Supplementary Table S3 includes p.A456V and p.A456G, indicating codon 456 substitutions are heterogeneous.
Still missing
- This substitution is not listed among the exact PM1-eligible variants in the local POLE framework.
Sources
vcep_p_a_t_h___2_5_0___3_2_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
PM5 A different substitution at the same codon, p.(Ala456Pro), is included in the local POLE hotspot set, but the same residue also shows other non-equivalent substitutions in the supplementary tables, including p.A456G and p.A456V. Because the local framework warns against extrapolating codon-level pathogenicity across substitutions, PM5 is not met. Details ▾Hide ▴
Evidence considered
- p.A456P is a framework-listed hotspot substitution.
- Supplementary Table S3 also lists p.A456G and p.A456V at the same residue.
Still missing
- No gene-specific rule supporting codon-level extrapolation for p.(Ala456Val) was identified.
Sources
vcep_p_a_t_h___2_5_0___3_2_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the benign stand-alone threshold of 1%. Details ▾Hide ▴
Rule
Generic benign population threshold: BA1 requires frequency >1%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the benign strong threshold of 0.3%. Details ▾Hide ▴
Rule
Generic benign population threshold: BS1 requires frequency >0.3%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 The local POLE BP4 rule is not met because León-Castillo Supplementary Table S3 lists p.A456V as likely disease causing, not likely benign, and the benign in silico result count is 0 rather than at least 4. Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: BP4_Supporting requires REVEL class likely benign and benign in silico results >=4.
Evidence considered
- Supplementary Table S3: A456V, REVEL class 'likely disease causing', benign in silico results = 0.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
Not assessed · 14 · no assessment recorded
PS2 No confirmed de novo data with verified maternity and paternity were identified, so PS2 was not assessed. Details ▾Hide ▴
Still missing
- No parental testing or de novo confirmation was available.
PS3 No validated variant-specific functional study demonstrating a damaging effect for p.(Ala456Val) was identified in the available evidence, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
- Functional-themed literature was triaged, but no variant-specific assay result for p.(Ala456Val) was retrieved.
Still missing
- No assay results specific to p.(Ala456Val) were identified.
Sources
PM3 No trans data with another pathogenic variant in a recessive disorder context were identified, so PM3 was not assessed. Details ▾Hide ▴
Still missing
- No phase or biallelic case data were available.
PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not assessed. Details ▾Hide ▴
Still missing
- No de novo report was available.
PP1 No segregation data were identified, so PP1 was not assessed. Details ▾Hide ▴
Still missing
- No family segregation studies were available.
PP2 Gene-level evidence required to determine whether missense variation is a common disease mechanism and benign missense variation is low was not identified, so PP2 was not assessed. Details ▾Hide ▴
Still missing
- No retrieved gene-level missense mechanism or constraint evidence specific to PP2.
PP4 No phenotype data sufficiently specific for a single genetic etiology were identified, so PP4 was not assessed. Details ▾Hide ▴
Still missing
- No individual-level phenotype or tumor-signature report was available for this case.
PP5 No reputable source classification for this exact variant was identified, so PP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No ClinVar result found.
Still missing
- This variant is absent from ClinVar.
Sources
BS2 No evidence showing this variant in healthy adult individuals at a frequency inconsistent with disease penetrance was identified, so BS2 was not assessed. Details ▾Hide ▴
Still missing
- No unaffected carrier data were available.
BS3 No validated variant-specific functional study demonstrating no damaging effect for p.(Ala456Val) was identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
- Functional-themed literature was triaged, but no benign functional assay result specific to p.(Ala456Val) was retrieved.
Still missing
- No well-established benign functional data for p.(Ala456Val) were identified.
Sources
BS4 No segregation data showing lack of cosegregation with disease were identified, so BS4 was not assessed. Details ▾Hide ▴
Still missing
- No family segregation evidence was available.
BP2 No phase data showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant were identified, so BP2 was not assessed. Details ▾Hide ▴
Still missing
- No phase information was available.
BP5 No alternate molecular explanation fully accounting for the phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴
Still missing
- No case-level phenotype or alternate diagnosis data were available.
BP6 No reputable source classified this exact variant as benign or likely benign, so BP6 was not assessed. Details ▾Hide ▴
Evidence considered
- No ClinVar result found.
Still missing
- This variant is absent from ClinVar.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants, so PVS1 is not applicable. Details ▾Hide ▴
Rule
ClinGen SVI PVS1 recommendations: generic PVS1 scaffold not applicable to this missense variant.
Evidence considered
- POLE is eligible for generic PVS1 fallback at the gene level.
- NM_006231.4:c.1367C>T is not a null variant and is not a canonical splice-site variant.
Sources
PM4 N/AThis is a missense substitution and not a protein length-changing variant, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala456Val).
Sources
case_summary_json
BP1 N/ABP1 is not applicable because POLE does not fit a disease model in which only truncating variants are expected to be pathogenic; the local POLE framework specifically addresses pathogenic missense variants. Details ▾Hide ▴
Evidence considered
- The local POLE framework is built for missense variants.
- POLE loss of function is also supported at the gene level.
Sources
final_classification_frameworkpvs1_gene_context
BP3 N/AThis is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala456Val).
Sources
case_summary_json
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala456Val).
- SpliceAI max delta score = 0.10.
Sources
case_summary_jsonspliceai ↗
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.1367C>T
- Protein (HGVS p.)
- NP_006222.2:p.(Ala456Val)
- GRCh38
- chr12:132673270 G>A
- GRCh37
- chr12:133249856 G>A
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in POLE
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis variant is listed in León-Castillo Supplementary Table S3 as p.A456V with REVEL classified as likely disease causing and 0 benign in silico results, which meets the local POLE PP3 rule. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.10, supporting interpretation as a missense effect rather than a splice-disrupting variant. Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: PP3_Supporting when the exact variant is in Table S2 or S3, REVEL class is likely disease causing, and benign in silico results are <=1.
Evidence considered
- Supplementary Table S3: A456V, REVEL class 'likely disease causing', benign in silico results = 0.
- SpliceAI max delta score = 0.10.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4spliceai ↗
BP4 The local POLE BP4 rule is not met because León-Castillo Supplementary Table S3 lists p.A456V as likely disease causing, not likely benign, and the benign in silico result count is 0 rather than at least 4. Details ▾Hide ▴
Rule
León-Castillo 2020 custom POLE framework: BP4_Supporting requires REVEL class likely benign and benign in silico results >=4.
Evidence considered
- Supplementary Table S3: A456V, REVEL class 'likely disease causing', benign in silico results = 0.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala456Val).
- SpliceAI max delta score = 0.10.
Sources
case_summary_jsonspliceai ↗
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
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
Captured gnomAD v4.1 source record
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
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006231.4%3Ac.1367C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133249856-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132673270-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.1367…
- OncoKB ↗www.oncokb.org/gene/POLE/A456V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=110791410
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57673561, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.