About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.4952+13C>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 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006231.4:c.4952+13C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, complete absence from large population databases supports PM2 at supporting strength (allele frequency <0.1%).
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
NM_006231.4:c.4952+13C>A is an intronic variant at position +13 of intron 37. SpliceAI predicts no splice impact (max delta score = 0.01, well below the 0.2 threshold for any splice-altering effect). All four delta scores (acceptor gain, acceptor loss, donor gain, donor loss) are ≤0.01. While BP7 was originally defined for synonymous variants, extended ACMG/AMP interpretations support its application to intronic variants at non-conserved positions where splicing algorithms predict no impact on native splicing or creation of a novel splice site.
Recorded classification: Uncertain significance
The León-Castillo et al. 2020 custom POLE gene-specific framework was used as primary authority for criterion adjudication; its final combination rules mirror generic ACMG/AMP 2015 (PMID:25741868). The only met criteria are PM2 at supporting strength (absent from gnomAD) and BP7 at supporting benign strength (SpliceAI predicts no splice impact). One pathogenic supporting and one benign supporting criterion offset each other. No combination rule for Pathogenic, Likely Pathogenic, Likely Benign, or Benign is satisfied. The variant falls into the default VUS category.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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.
26 criteria with recorded statuses: 2 met · 18 not met · 1 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
NM_006231.4:c.4952+13C>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
SpliceAI predicts no splice impact with a maximum delta score of 0.01, supporting a benign computational interpretation (BP7_Supporting).
The variant is an intronic substitution at position +13 of intron 37, outside the canonical splice consensus. PVS1 is not applicable; no null variant mechanism is supported.
The variant is absent from ClinVar with no published literature describing this exact variant. No functional, segregation, case-control, or de novo data are available.
The León-Castillo et al. 2020 custom POLE framework (local gene-specific framework) covers PM1, PS4, PP3, and BP4 for exonuclease-domain missense variants only. This intronic variant falls outside the framework's scope, and none of the four customized criteria are met under the framework's rules.
Overall evidence is insufficient for classification. PM2_Supporting and BP7_Supporting provide offsetting weak pathogenic and benign signals. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_006231.4:c.4952+13C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, complete absence from large population databases supports PM2 at supporting strength (allele frequency <0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BP7 SupportingNM_006231.4:c.4952+13C>A is an intronic variant at position +13 of intron 37. SpliceAI predicts no splice impact (max delta score = 0.01, well below the 0.2 threshold for any splice-altering effect). All four delta scores (acceptor gain, acceptor loss, donor gain, donor loss) are ≤0.01. While BP7 was originally defined for synonymous variants, extended ACMG/AMP interpretations support its application to intronic variants at non-conserved positions where splicing algorithms predict no impact on native splicing or creation of a novel splice site. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01 — no predicted splice alteration
- All individual delta scores ≤0.01 (DS_AG=0.01
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- Intronic variant at +13 position
- not at splice consensus
Sources
Not met · 18 · evaluated, threshold not reached
PVS1 NM_006231.4:c.4952+13C>A is an intronic substitution at position +13 of intron 37, outside the canonical splice consensus (±1,2). PVS1 variant assessment confirms this variant does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical splice). SpliceAI predicts no significant splice impact (max delta score = 0.01). PVS1 is not applicable for this variant under generic ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Intronic variant at +13 position
- not at canonical splice consensus
- SpliceAI max delta score 0.01
- well below pathogenic thresholds
- PVS1 variant assessment bucket: 'other'
- apply_generic_pvs1_framework: false
Sources
PS1 No known pathogenic variant has been reported at this exact nucleotide position (c.4952+13). This variant is absent from ClinVar and no literature exists reporting a different pathogenic change at the same nucleotide. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar — no known pathogenic variant at this nucleotide position
Sources
PS3 No functional data exists for NM_006231.4:c.4952+13C>A. No variant-specific or systematically characterized range functional studies were identified. The variant is intronic (+13) and not expected to alter protein function; no experimental functional assays have been performed for this variant. Details ▾Hide ▴
Evidence considered
- Variant is intronic (+13)
- not amenable to protein-level functional assays
- No functional studies identified in literature or curated databases
- Not listed in León-Castillo et al. supplementary tables (missense-only)
Still missing
- No functional data available for this intronic variant
PS4 The León-Castillo custom POLE framework restricts PS4 to specific exonuclease-domain hotspot missense variants with ≥10 combined COSMIC+TCGA cases. This variant is an intronic substitution, not a missense variant, and is absent from all León-Castillo supplementary tables. No case-control or cohort enrichment data exists. Falls outside custom framework scope; under generic ACMG, no evidence for enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not in León-Castillo exonuclease-domain framework scope
- Absent from COSMIC and León-Castillo Table S1 recurrent variant lists
- No case-control or cohort enrichment data available
Sources
vcep_path_250_323vcep_path_250_323_s002
PM1 The León-Castillo custom POLE framework defines PM1 exclusively for specific exonuclease-domain missense variants. This variant is an intronic substitution at position +13 of intron 37, which is outside the exonuclease domain and does not affect any known functional domain or mutational hotspot. The variant does not correspond to any of the five established hotspot residues (P286, V411, S297, A456, S459) or the extended moderate/supporting PM1 list in the custom framework. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not in exonuclease domain
- Not one of the five established hotspot residues in León-Castillo framework
- Variant not present in León-Castillo Table S1 recurrent variant list
Sources
vcep_path_250_323vcep_path_250_323_s002vcep_path_250_323_s001
PP1 No segregation data available. Cosegregation with disease in multiple affected family members has not been reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
PP3 The León-Castillo custom POLE framework restricts PP3 to exact missense variants appearing in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This variant is intronic, not missense, and is absent from both supplementary tables. Under generic ACMG, multiple lines of computational evidence supporting a deleterious effect are required. SpliceAI predicts no splice impact (max delta 0.01). REVEL and BayesDel scores are not applicable for this intronic variant. No computational tools support pathogenicity. Details ▾Hide ▴
Evidence considered
- Variant not present in León-Castillo Table S2 or S3 (missense-only tables)
- SpliceAI max delta 0.01: no predicted splice alteration
- REVEL not applicable (not a missense variant)
- BayesDel not applicable
Sources
PP4 No patient phenotype data is available to assess whether the variant's phenotype is highly specific for a disease. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical data available
PP5 NM_006231.4:c.4952+13C>A is absent from ClinVar. No 3-star expert panel classification exists for this variant. PP5 requires a reputable source (3-star ClinVar expert panel) classifying the variant as pathogenic. Details ▾Hide ▴
BA1 NM_006231.4:c.4952+13C>A is absent from all gnomAD databases (allele frequency = 0%). BA1 requires an allele frequency >1% in population databases. This variant is too rare to meet BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 allele frequency: 0%
- gnomAD v4.1 allele frequency: 0%
- gnomAD-Canada allele frequency: 0%
- All frequencies well below BA1 threshold of >1%
Sources
BS1 NM_006231.4:c.4952+13C>A is absent from all gnomAD databases (allele frequency = 0%). BS1 requires an allele frequency >0.3% in population databases. The variant is too rare to meet BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 allele frequency: 0%
- gnomAD v4.1 allele frequency: 0%
- All frequencies below BS1 threshold of >0.3%
Sources
BS2 No observation of this variant in a homozygous state or in trans with a pathogenic variant in healthy controls. No data available to assess BS2. Details ▾Hide ▴
Still missing
- No homozygous or trans observation data available
BS3 No functional studies, either in vivo or in vitro, have been performed for NM_006231.4:c.4952+13C>A demonstrating no damaging effect on protein function or splicing. BS3 requires well-established functional studies showing no deleterious effect. Details ▾Hide ▴
Still missing
- No functional studies available for this variant
BS4 No segregation data available to demonstrate lack of cosegregation with disease in affected family members. BS4 requires observation of the variant in healthy family members failing to segregate with disease. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data available on whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant. BP2 requires specific phase information that is not available. Details ▾Hide ▴
Still missing
- No phase or trans/cis observation data available
BP4 The León-Castillo custom POLE framework restricts BP4 to exact missense variants in Tables S2/S3 with REVEL 'Likely benign' and ≥4 benign in silico results. This intronic variant is absent from those tables. Under generic ACMG, BP4 requires multiple lines of computational evidence suggesting no impact. The only applicable tool (SpliceAI) shows no splice effect (max delta 0.01), but a single tool does not constitute multiple independent lines of computational evidence required for BP4. Details ▾Hide ▴
Evidence considered
- Variant not in León-Castillo Tables S2/S3 (missense-only)
- SpliceAI max delta 0.01 — single line of benign evidence
- insufficient for BP4 'multiple lines' requirement
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease. BP5 requires the variant to be found in a patient with an alternate established cause of their phenotype. Details ▾Hide ▴
Still missing
- No cases with alternate molecular diagnosis available
BP6 NM_006231.4:c.4952+13C>A is absent from ClinVar. No 3-star expert panel classification exists for this variant. BP6 requires a reputable source (3-star ClinVar expert panel) classifying the variant as benign. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PM6 No de novo report for NM_006231.4:c.4952+13C>A was identified in any source. PM6 requires a confirmed de novo observation (with maternity and paternity confirmed) for this specific variant. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ANo de novo data available. De novo confirmation requires parental testing results for this variant, which have not been reported in any source. Details ▾Hide ▴
Still missing
- No parental testing or trio data available
PM5 N/AVariant is intronic (c.4952+13C>A) with no protein consequence (NP_006222.2:p.?). Unable to parse missense residue context for same-residue comparator search. PM5 candidate harvesting was automatically skipped as classic same-residue semantics cannot be safely confirmed. Details ▾Hide ▴
Evidence considered
- Intronic variant with unknown protein consequence (p.?)
- PM5 candidate harvesting returned 0 candidates
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. NM_006231.4:c.4952+13C>A is an intronic substitution, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_006231.4:c.4952+13C>A is an intronic substitution, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/AVariant is intronic with no protein consequence (NP_006222.2:p.?). Criterion is not applicable as there is no amino acid residue to assess for a different pathogenic missense change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.4952+13C>A
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132642493 G>T
- GRCh37
- chr12:133219079 G>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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
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
BP7 SupportingNM_006231.4:c.4952+13C>A is an intronic variant at position +13 of intron 37. SpliceAI predicts no splice impact (max delta score = 0.01, well below the 0.2 threshold for any splice-altering effect). All four delta scores (acceptor gain, acceptor loss, donor gain, donor loss) are ≤0.01. While BP7 was originally defined for synonymous variants, extended ACMG/AMP interpretations support its application to intronic variants at non-conserved positions where splicing algorithms predict no impact on native splicing or creation of a novel splice site. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01 — no predicted splice alteration
- All individual delta scores ≤0.01 (DS_AG=0.01
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.0)
- Intronic variant at +13 position
- not at splice consensus
Sources
PP3 The León-Castillo custom POLE framework restricts PP3 to exact missense variants appearing in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This variant is intronic, not missense, and is absent from both supplementary tables. Under generic ACMG, multiple lines of computational evidence supporting a deleterious effect are required. SpliceAI predicts no splice impact (max delta 0.01). REVEL and BayesDel scores are not applicable for this intronic variant. No computational tools support pathogenicity. Details ▾Hide ▴
Evidence considered
- Variant not present in León-Castillo Table S2 or S3 (missense-only tables)
- SpliceAI max delta 0.01: no predicted splice alteration
- REVEL not applicable (not a missense variant)
- BayesDel not applicable
Sources
BP4 The León-Castillo custom POLE framework restricts BP4 to exact missense variants in Tables S2/S3 with REVEL 'Likely benign' and ≥4 benign in silico results. This intronic variant is absent from those tables. Under generic ACMG, BP4 requires multiple lines of computational evidence suggesting no impact. The only applicable tool (SpliceAI) shows no splice effect (max delta 0.01), but a single tool does not constitute multiple independent lines of computational evidence required for BP4. Details ▾Hide ▴
Evidence considered
- Variant not in León-Castillo Tables S2/S3 (missense-only)
- SpliceAI max delta 0.01 — single line of benign evidence
- insufficient for BP4 'multiple lines' requirement
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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.4952%2B13C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133219079-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132642493-G-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132642493-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.4952…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.4952+13C%3EA
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.
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 = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).