About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.5312C>T, p.(Thr1771Met)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (0.00399%, 10/250702 alleles) and gnomAD v4.1 AF 4.09054e-05 (0.00409%, 66/1613480 alleles), both below the project's PM2 threshold of 0.1%, with no homozygotes reported.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
The León-Castillo et al. 2020 custom POLE framework was used as the applicable final-classification framework; it customizes selected POLE criterion specifications while retaining standard ACMG/AMP 2015 final combination 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
66 / 1,613,480 alleles
gnomAD v4.1: 66 / 1,613,480 alleles. Recorded AF 4.09054e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9888e-05; MAF= 0.00399%, 10/250702 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163132; MAF= 0.01631%, 1/6130 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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: 1 met · 4 not met · 16 not assessed · 7 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.5312C>T (p.Thr1771Met) variant has been observed in somatic cancers in COSMIC (COSV57679989, n=2) and has been reported in ClinVar as a variant of uncertain significance.
The variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (10/250702) and gnomAD v4.1 AF 4.09054e-05 (66/1613480), with no homozygotes reported; these values are below the PM2 threshold of 0.1% and below the BS1 and BA1 thresholds of 0.3% and 1%, respectively.
No validated variant-specific functional assay evidence was identified for p.(Thr1771Met).
SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178; however, the variant is not represented in the León-Castillo POLE supplementary computational tables, so the custom POLE PP3 and BP4 rules were not applied.
No criteria match.
Met · 1
PM2 ModerateThis variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (0.00399%, 10/250702 alleles) and gnomAD v4.1 AF 4.09054e-05 (0.00409%, 66/1613480 alleles), both below the project's PM2 threshold of 0.1%, with no homozygotes reported. Details ▾Hide ▴
Rule
Generic ACMG fallback population rarity assessment using project default PM2 threshold (<0.1%).
Evidence considered
- gnomAD v2.1 AF 3.9888e-05; 10/250702 alleles; homozygotes = 0.
- gnomAD v4.1 AF 4.09054e-05; 66/1613480 alleles; homozygotes = 0.
Sources
Not met · 4 · evaluated, threshold not reached
PS4 Under the custom POLE framework, PS4 is restricted to exact variants recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined count at least 10 and belonging to the established pathogenic set. p.(Thr1771Met) is not included in that set, and COSMIC shows only 2 somatic observations, which is below the framework requirement. Details ▾Hide ▴
Rule
Custom POLE PS4_Supporting applies only to exact variants recurrent in both COSMIC and TCGA EC cohorts with combined count >=10 and belonging to the established pathogenic set.
Evidence considered
- COSMIC COSV57679989 somatic count = 2.
- León-Castillo Supplementary Table S1 does not list p.(Thr1771Met) among PS4-eligible recurrent established pathogenic variants.
Still missing
- No germline case-control enrichment data were identified.
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 custom POLE framework does not assign PM1 by domain location alone and limits PM1 to specific exact substitutions from León-Castillo et al. p.(Thr1771Met) is not one of the exact PM1-eligible hotspot, pathogenic non-hotspot, or uncertain-tier recurrent substitutions, and Cancer Hotspots did not show a statistically significant hotspot at residue T1771. Details ▾Hide ▴
Rule
Custom POLE PM1 is restricted to exact substitutions enumerated in León-Castillo et al.; domain membership alone is insufficient.
Evidence considered
- Cancer Hotspots: no hotspot row found for POLE T1771.
- León-Castillo PM1-eligible exact variant lists do not include T1771M.
Sources
hotspots ↗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
BA1 Population frequency is below the benign stand-alone threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both well below the BA1 threshold of 1%. Details ▾Hide ▴
Rule
Generic ACMG fallback BA1 threshold >1%.
Evidence considered
- gnomAD v2.1 AF 0.00399%.
- gnomAD v4.1 AF 0.00409%.
Sources
BS1 Population frequency is below the strong benign threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both below the BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
Generic ACMG fallback BS1 threshold >0.3%.
Evidence considered
- gnomAD v2.1 AF 0.00399%.
- gnomAD v4.1 AF 0.00409%.
Sources
Not assessed · 16 · no assessment recorded
PS1 No evidence was identified showing that a different nucleotide change causing the same amino acid substitution p.(Thr1771Met) is established as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar lists this specific variant as uncertain significance.
Still missing
- No same-amino-acid pathogenic comparison variant was retrieved.
Sources
PS2 No confirmed de novo occurrence with parental confirmation was identified. Details ▾Hide ▴
Still missing
- No trio or parental testing data were retrieved.
PS3 No validated variant-specific functional studies were identified showing a damaging effect for p.(Thr1771Met). Details ▾Hide ▴
Evidence considered
- OncoKB has not reviewed this specific variant.
Still missing
- No variant-specific functional assay data were retrieved.
Sources
PM5 No evidence was identified for a different pathogenic or likely pathogenic missense change affecting the same amino acid residue Thr1771. Details ▾Hide ▴
Evidence considered
- ClinVar evidence retrieved for this variant does not establish a pathogenic alternate missense at the same residue.
Still missing
- No pathogenic alternate missense change at codon 1771 was retrieved.
Sources
PM6 No assumed de novo occurrence data were identified. Details ▾Hide ▴
Still missing
- No de novo report without full parental confirmation was retrieved.
PP1 No segregation data were identified to show co-segregation with disease in affected relatives. Details ▾Hide ▴
Still missing
- No family segregation data were retrieved.
PP2 No gene-level evidence was retrieved showing that POLE has a low rate of benign missense variation together with missense variants as a common disease mechanism in a way that would support PP2 for this review. Details ▾Hide ▴
Still missing
- No gene-level PP2 framework was retrieved.
PP3 The custom POLE PP3 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with a REVEL class of 'likely disease causing' and no more than 1 benign in silico result. p.(Thr1771Met) was not found in those tables, so the custom PP3 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense PP3 threshold set was not retrieved. Details ▾Hide ▴
Rule
Custom POLE PP3 applies only if the exact variant is present in Table S2 or S3 with REVEL class 'likely disease causing' and <=1 benign in silico result.
Evidence considered
- SpliceAI max delta score = 0.04.
- Local REVEL score = 0.178.
- Variant absent from León-Castillo Tables S2 and S3.
Still missing
- The variant is absent from the custom POLE supplementary computational tables.
- No separate generic missense PP3 threshold set was retrieved.
Sources
spliceai ↗vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
PP4 No phenotype-specific clinical presentation or tumor signature evidence was identified that would support a highly specific POLE-associated presentation for this variant. Details ▾Hide ▴
Evidence considered
- The retrieved POLE paper provides general ultramutated-signature context but no variant-specific phenotype evidence for p.(Thr1771Met).
Still missing
- No phenotype details or POLE ultramutated tumor-signature evidence were retrieved.
Sources
vcep_p_a_t_h___2_5_0___3_2_3
BS2 No evidence was identified showing this variant in a sufficient number of well-characterized unaffected individuals for BS2. Details ▾Hide ▴
Still missing
- No unaffected-carrier dataset sufficient for BS2 was retrieved.
BS3 No validated variant-specific functional studies were identified showing no damaging effect for p.(Thr1771Met). Details ▾Hide ▴
Evidence considered
- OncoKB has not reviewed this specific variant.
Still missing
- No variant-specific benign functional assay data were retrieved.
Sources
BS4 No nonsegregation data were identified. Details ▾Hide ▴
Still missing
- No family nonsegregation data were retrieved.
BP1 No gene-specific framework was retrieved supporting BP1 for missense variation in POLE. Details ▾Hide ▴
Still missing
- No BP1-supporting gene-level framework was retrieved.
BP2 No phase or co-occurrence data were identified to support BP2. Details ▾Hide ▴
Still missing
- No cis/trans co-occurrence data were retrieved.
BP4 The custom POLE BP4 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and at least 4 benign in silico results. p.(Thr1771Met) was not found in those tables, so the custom BP4 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense BP4 threshold set was not retrieved. Details ▾Hide ▴
Rule
Custom POLE BP4 applies only if the exact variant is present in Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and >=4 benign in silico results.
Evidence considered
- SpliceAI max delta score = 0.04.
- Local REVEL score = 0.178.
- Variant absent from León-Castillo Tables S2 and S3.
Still missing
- The variant is absent from the custom POLE supplementary computational tables.
- No separate generic missense BP4 threshold set was retrieved.
Sources
spliceai ↗vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
BP5 No alternate molecular diagnosis or other variant explaining the phenotype was identified. Details ▾Hide ▴
Still missing
- No alternative molecular diagnosis data were retrieved.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.5312C>T predicts a missense change, p.(Thr1771Met), rather than a null variant, and the generic PVS1 assessment does not place this variant in a nonsense, frameshift, or canonical splice category, so PVS1 is not applicable. Details ▾Hide ▴
Rule
PVS1 applies to qualifying loss-of-function variants; this variant is a missense substitution.
Evidence considered
- Protein consequence NP_006222.2:p.(Thr1771Met).
- Generic PVS1 scaffold: apply_generic_pvs1_framework = false.
Sources
pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 is a recessive trans-observation criterion, and no qualifying recessive trans observations were identified for this POLE missense variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a missense substitution and does not cause a protein length change or an in-frame insertion or deletion, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence NP_006222.2:p.(Thr1771Met).
Sources
pvs1_variant_assessment
PP5 N/APP5 was not used because assertion-only external classifications are not applied in this review framework. Details ▾Hide ▴
Rule
Assertion-only criteria are not used.
Evidence considered
- ClinVar classification is uncertain significance.
Sources
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions without known function, and this variant is a missense substitution, so BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 was not used because assertion-only external classifications are not applied in this review framework. Details ▾Hide ▴
Rule
Assertion-only criteria are not used.
Evidence considered
- ClinVar classification is uncertain significance.
Sources
BP7 N/ABP7 applies to synonymous or certain intronic variants predicted to have no splicing impact, and this variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.5312C>T
- Protein (HGVS p.)
- NP_006222.2:p.(Thr1771Met)
- GRCh38
- chr12:132641713 G>A
- GRCh37
- chr12:133218299 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
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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
66 / 1,613,480 alleles
AF 4.09e-05 · 0 homozygotes · FAF 4.02e-05
gnomAD v2.1
10 / 250,702 alleles
AF 3.99e-05 · 0 homozygotes · FAF 2.86e-05
By genetic ancestry
gnomAD v4.1
AF 4.1e-05 · 66 / 1,613,480 alleles · 0 hom · FAF 4e-05
| Middle Eastern1 / 6,082 | 0.00016 |
| European (non-Finnish)60 / 1,180,026 | 5.1e-05 |
| Remaining individuals2 / 62,482 | 3.2e-05 |
| African/African American2 / 74,932 | 2.7e-05 |
| Admixed American1 / 60,004 | 1.7e-05 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4e-05 · 10 / 250,702 alleles · 0 hom · FAF 2.9e-05
| Remaining individuals1 / 6,130 | 0.00016 |
| European (non-Finnish)7 / 113,630 | 6.2e-05 |
| East Asian1 / 18,390 | 5.4e-05 |
| Admixed American1 / 34,584 | 2.9e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.09054e-05; MAF= 0.00409%, 66/1613480 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016442; MAF= 0.01644%, 1/6082 alleles, homozygotes = 0); grpmax FAF= 4.019e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9888e-05; MAF= 0.00399%, 10/250702 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163132; MAF= 0.01631%, 1/6130 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 The custom POLE PP3 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with a REVEL class of 'likely disease causing' and no more than 1 benign in silico result. p.(Thr1771Met) was not found in those tables, so the custom PP3 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense PP3 threshold set was not retrieved. Details ▾Hide ▴
Rule
Custom POLE PP3 applies only if the exact variant is present in Table S2 or S3 with REVEL class 'likely disease causing' and <=1 benign in silico result.
Evidence considered
- SpliceAI max delta score = 0.04.
- Local REVEL score = 0.178.
- Variant absent from León-Castillo Tables S2 and S3.
Still missing
- The variant is absent from the custom POLE supplementary computational tables.
- No separate generic missense PP3 threshold set was retrieved.
Sources
spliceai ↗vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
BP4 The custom POLE BP4 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and at least 4 benign in silico results. p.(Thr1771Met) was not found in those tables, so the custom BP4 rule cannot be applied. SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178, but a separate generic missense BP4 threshold set was not retrieved. Details ▾Hide ▴
Rule
Custom POLE BP4 applies only if the exact variant is present in Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and >=4 benign in silico results.
Evidence considered
- SpliceAI max delta score = 0.04.
- Local REVEL score = 0.178.
- Variant absent from León-Castillo Tables S2 and S3.
Still missing
- The variant is absent from the custom POLE supplementary computational tables.
- No separate generic missense BP4 threshold set was retrieved.
Sources
spliceai ↗vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4final_classification_framework
BP7 N/ABP7 applies to synonymous or certain intronic variants predicted to have no splicing impact, and this variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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
66 / 1,613,480 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
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/variation/405600/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133218299-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132641713-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.5312…
- OncoKB ↗www.oncokb.org/gene/POLE/T1771M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=110783829
- 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
This variant is present in gnomAD v4.1 (AF= 4.09054e-05; MAF= 0.00409%, 66/1613480 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016442; MAF= 0.01644%, 1/6082 alleles, homozygotes = 0); grpmax FAF= 4.019e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9888e-05; MAF= 0.00399%, 10/250702 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163132; MAF= 0.01631%, 1/6130 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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; COSV57679989, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.