About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.-11C>T, 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 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
PM2Supporting
PM2 · supporting
NM_006231.4:c.-11C>T is present at extremely low frequency in population databases. gnomAD v4.1 reports 3 alleles out of 1,498,064 (AF 2.0e-06, 0.00020%), all in the South Asian subpopulation (SAS AF 3.75e-05). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The total allele frequency is well below the 0.1% PM2 threshold, consistent with absence from controls at sufficient depth.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Only PM2 is met at supporting strength (gnomAD v4.1: 3/1,498,064 alleles, AF 0.00020%). All other criteria are not_met or not_applicable. Under the Leó-Castillo 2020 custom POLE framework combination rules (which mirror standard ACMG/AMP 2015 thresholds), a single supporting criterion does not satisfy any classification tier: Pathogenic requires at minimum PVS1+2Supporting or 2Strong; Likely Pathogenic requires at minimum PVS1+1Moderate or 1Strong+2Supporting or 3Moderate; Benign requires BA1 or 2 Strong benign; Likely Benign requires 1 Strong benign + 1 Supporting benign or 2 Supporting benign. With only PM2_Supporting met and no benign criteria, the variant defaults to Variant of Uncertain Significance.
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
3 / 1,498,064 alleles
gnomAD v4.1: 3 / 1,498,064 alleles. Recorded AF 2.00258e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 19 not met · 0 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
NM_006231.4:c.-11C>T is a non-coding promoter/5'UTR substitution 11 bases upstream of the ATG start codon. It is present at extremely low frequency in gnomAD v4.1 (3/1,498,064 alleles, AF 0.00020%, all South Asian) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level.
PVS1 does not apply as this is a non-coding variant and not a null variant. The León-Castillo 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) apply only to exonuclease-domain missense variants and do not extend to this promoter variant.
SpliceAI predicts no splice impact (max delta 0.00). No functional studies, segregation data, de novo reports, case-control data, or ClinVar classifications are available for this variant.
No publications specifically mention NM_006231.4:c.-11C>T. Five papers reviewed in the PVS1 gene context support POLE loss-of-function as a germline disease mechanism at the gene level but do not report this specific variant.
With only PM2_Supporting met, this variant does not meet any ACMG/AMP 2015 classification threshold (requires ≥2 pathogenic supporting criteria with additional evidence, or BS1/BA1 thresholds for benign classification). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingNM_006231.4:c.-11C>T is present at extremely low frequency in population databases. gnomAD v4.1 reports 3 alleles out of 1,498,064 (AF 2.0e-06, 0.00020%), all in the South Asian subpopulation (SAS AF 3.75e-05). The variant is absent from gnomAD v2.1 and gnomAD-Canada. The total allele frequency is well below the 0.1% PM2 threshold, consistent with absence from controls at sufficient depth. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 3/1
- 498
- 064 alleles (AF 0.00020%
- all South Asian)
- gnomAD v2.1: absent
- gnomAD-Canada: absent
Sources
Not met · 19 · evaluated, threshold not reached
PVS1 NM_006231.4:c.-11C>T is a promoter/5'UTR substitution 11 bases upstream of the ATG start codon. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework does not apply to non-coding promoter variants, and the pvs1_variant_assessment confirms 'apply_generic_pvs1_framework: false' with variant_bucket 'other'. Details ▾Hide ▴
Evidence considered
- Non-coding promoter variant
- not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS2 No de novo data available for NM_006231.4:c.-11C>T. The variant is absent from ClinVar and no publications report de novo observations. Details ▾Hide ▴
Evidence considered
- No de novo evidence found in ClinVar
- literature
- or other sources.
Still missing
- No de novo testing data available.
PS3 No functional studies are available for NM_006231.4:c.-11C>T. In silico tools (REVEL, BayesDel) do not score non-coding variants; SpliceAI predicts no splice impact (max delta 0.00). No well-established in vitro or in vivo functional assays have been performed for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 — no splice impact predicted. No functional assay data available.
Still missing
- No functional characterization of this promoter variant has been performed.
Sources
PS4 The León-Castillo 2020 custom POLE PS4 framework applies only to exonuclease-domain missense variants recurrent in COSMIC/TCGA endometrial carcinoma cohorts. NM_006231.4:c.-11C>T is a non-coding promoter variant, absent from COSMIC, and not represented in the León-Castillo supplementary recurrence tables. No germline case-control enrichment data are available. Details ▾Hide ▴
Evidence considered
- Variant is non-coding
- León-Castillo PS4 rules do not apply. Absent from COSMIC. No germline case-control data.
Still missing
- No case-control or cohort enrichment data for this variant.
Sources
vcep_path_250_323_s002
PM1 The León-Castillo 2020 custom POLE PM1 framework assigns PM1 only to specific exonuclease-domain missense variants (e.g., P286R, V411L, S297F, A456P, S459F at strong; F367S, L424I at moderate; A465V, L424V at supporting). NM_006231.4:c.-11C>T is a non-coding promoter variant — it is not a missense variant, is not within the exonuclease domain, and is absent from the supplementary tables. The generic ACMG/AMP PM1 also does not apply: the c.-11 5'UTR position is not an established mutational hotspot or critical functional domain without benign variation for POLE. Details ▾Hide ▴
Evidence considered
- Non-coding promoter variant
- not in exonuclease domain. No PM1 eligibility under León-Castillo custom or generic ACMG rules.
Sources
vcep_path_250_323vcep_path_250_323_s002
PM6 No de novo evidence is available for NM_006231.4:c.-11C>T. No publications report a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data found in any source.
Still missing
- No de novo testing data available.
PP1 No segregation data are available for NM_006231.4:c.-11C>T. No family studies or co-segregation analyses have been reported. Details ▾Hide ▴
Evidence considered
- No segregation or family study data available.
Still missing
- No segregation analysis performed.
PP3 The León-Castillo 2020 custom PP3 rule requires the variant to be a missense variant present in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), and REVEL/BayesDel do not score non-coding variants. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 — no predicted splice impact
- REVEL/BayesDel not applicable to non-coding variants
- León-Castillo Tables S2/S3: variant not present (tables are missense-only)
Still missing
- No computational tools score promoter variants for deleteriousness.
Sources
PP4 No phenotype specificity data are available. No evidence that NM_006231.4:c.-11C>T is enriched in patients with a specific POLE-associated phenotype compared to controls. Details ▾Hide ▴
Evidence considered
- No phenotype-specific data available.
Still missing
- No phenotype-genotype correlation data.
PP5 No reputable source (ClinVar, expert panel, published report) has classified NM_006231.4:c.-11C>T as pathogenic. The variant is absent from ClinVar and all reviewed publications. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar and all literature sources reviewed.
Still missing
- No prior classification by any reputable source.
Sources
BA1 gnomAD v4.1 allele frequency is 0.00020% (grpmax FAF 9.95e-06), well below the 1% BA1 threshold. The variant is too rare to be considered a common benign polymorphism. Details ▾Hide ▴
BS1 gnomAD v4.1 allele frequency is 0.00020%, below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
BS2 No data on observation of NM_006231.4:c.-11C>T in healthy adults for a fully penetrant early-onset disorder. The three gnomAD v4.1 alleles are from a general population cohort without phenotype annotation sufficient for BS2 determination. Details ▾Hide ▴
Evidence considered
- No phenotype-annotated healthy adult carrier data available.
Still missing
- No data on variant presence in healthy controls with phenotype ascertainment.
BS3 No well-established functional studies demonstrate no deleterious effect of NM_006231.4:c.-11C>T. No in vitro or in vivo assays have characterized this promoter variant. Details ▾Hide ▴
Evidence considered
- No functional characterization studies available.
Still missing
- No functional studies assessing promoter activity.
BS4 No segregation data are available to assess lack of segregation with disease for NM_006231.4:c.-11C>T. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation studies.
BP2 No evidence that NM_006231.4:c.-11C>T has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant regardless of inheritance pattern. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available.
Still missing
- No phasing data with known pathogenic variants.
BP4 The León-Castillo 2020 custom BP4 rule applies only to missense variants in Supplementary Tables S2/S3 with REVEL class 'likely benign' and ≥4 benign in silico results. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), but this represents a single line of computational evidence and does not meet the 'multiple lines' requirement of generic BP4. REVEL/BayesDel are not applicable to non-coding variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 — single line only
- insufficient for BP4
- REVEL/BayesDel not applicable to non-coding variants
Still missing
- Insufficient computational evidence for BP4
- only SpliceAI available for non-coding variants.
Sources
BP5 No evidence that NM_006231.4:c.-11C>T has been observed in a case with an alternative molecular cause for disease. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular causes in carriers.
Still missing
- No case-level data with alternative diagnoses.
PS5 No ClinVar submissions, no expert panel classifications, and no publications report NM_006231.4:c.-11C>T as a pathogenic variant. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar. No published pathogenic assertion found.
Still missing
- No established source classifies this variant as pathogenic.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANon-coding variant; no amino acid change to compare with alternative nucleotide changes. Details ▾Hide ▴
Evidence considered
- c.-11C>T is upstream of the coding sequence
- PS1 requires a same amino acid change from a different nucleotide substitution.
PM5 N/ANon-coding variant does not alter an amino acid residue, so a same-residue pathogenic comparator cannot exist. pm5_candidates.json confirms PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Non-coding variant
- no protein residue for comparator analysis.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. NM_006231.4:c.-11C>T is a non-coding promoter variant, not a missense change. Even if POLE has a low rate of benign missense variation, this criterion is restricted to missense variants. Details ▾Hide ▴
Evidence considered
- Non-coding variant
- PP2 is restricted to missense variants.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_006231.4:c.-11C>T is a non-coding promoter variant. Even though POLE truncating variants may be a disease mechanism, BP1 requires a missense variant to trigger. Details ▾Hide ▴
Evidence considered
- Non-coding promoter variant
- BP1 applies only to missense variants.
BP3 N/ASkipped per instructions. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 applies to synonymous (silent) variants for which a reputable source classifies the variant as benign. NM_006231.4:c.-11C>T is a non-coding promoter variant, not a synonymous coding variant. Even if extended by analogy, no reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- Non-coding variant
- BP6 is defined for synonymous variants.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006231.4:c.-11C>T is a non-coding 5'UTR/promoter variant, not a synonymous coding variant. While SpliceAI predicts no splice impact (max delta 0.00), the criterion is strictly defined for synonymous coding variants. Details ▾Hide ▴
Evidence considered
- Non-coding 5'UTR variant
- BP7 is defined for synonymous coding variants only.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.-11C>T
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132687326 G>A
- GRCh37
- chr12:133263912 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
3 / 1,498,064 alleles
AF 2e-06 · 0 homozygotes · FAF 9.95e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2e-06 · 3 / 1,498,064 alleles · 0 hom · FAF 9.9e-06
| South Asian3 / 80,062 | 3.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.00258e-06; MAF= 0.00020%, 3/1498064 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.7471e-05; MAF= 0.00375%, 3/80062 alleles, homozygotes = 0); grpmax FAF= 9.95e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 The León-Castillo 2020 custom PP3 rule requires the variant to be a missense variant present in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), and REVEL/BayesDel do not score non-coding variants. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 — no predicted splice impact
- REVEL/BayesDel not applicable to non-coding variants
- León-Castillo Tables S2/S3: variant not present (tables are missense-only)
Still missing
- No computational tools score promoter variants for deleteriousness.
Sources
BP4 The León-Castillo 2020 custom BP4 rule applies only to missense variants in Supplementary Tables S2/S3 with REVEL class 'likely benign' and ≥4 benign in silico results. NM_006231.4:c.-11C>T is a non-coding variant absent from these tables. Under generic ACMG/AMP fallback, SpliceAI predicts no splice impact (max delta 0.00), but this represents a single line of computational evidence and does not meet the 'multiple lines' requirement of generic BP4. REVEL/BayesDel are not applicable to non-coding variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 — single line only
- insufficient for BP4
- REVEL/BayesDel not applicable to non-coding variants
Still missing
- Insufficient computational evidence for BP4
- only SpliceAI available for non-coding variants.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006231.4:c.-11C>T is a non-coding 5'UTR/promoter variant, not a synonymous coding variant. While SpliceAI predicts no splice impact (max delta 0.00), the criterion is strictly defined for synonymous coding variants. Details ▾Hide ▴
Evidence considered
- Non-coding 5'UTR variant
- BP7 is defined for synonymous coding variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
3 / 1,498,064 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006231.4%3Ac.-11C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133263912-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132687326-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132687326-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.-11C…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.-11C%3ET
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= 2.00258e-06; MAF= 0.00020%, 3/1498064 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.7471e-05; MAF= 0.00375%, 3/80062 alleles, homozygotes = 0); grpmax FAF= 9.95e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).