About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.6531+19G>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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006231.4:c.6531+19G>T is completely absent from all queried population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP criteria, complete absence from large population cohorts supports PM2 at the supporting level. Note that coverage of deep intronic variants in exome-based datasets may be incomplete, but absence across both exome and genome resources is consistent with a very rare variant.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.02, where DS_AG=0.0, DS_AL=0.0, DS_DG=0.0, DS_DL=0.02; all well below the 0.10 threshold). While BP4 typically requires multiple lines of computational evidence, SpliceAI is the primary and most relevant computational tool for assessing intronic variants near splice junctions, and its prediction supports no functional impact on splicing.
Recorded classification: Uncertain significance
One supporting pathogenic criterion (PM2: variant absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada) and one supporting benign criterion (BP4: SpliceAI max delta score = 0.02 predicts no splicing impact). The combination of 1 supporting pathogenic + 1 supporting benign does not satisfy any Pathogenic, Likely Pathogenic, Likely Benign, or Benign threshold under the ACMG/AMP 2015 combination rules as adopted by the Leon-Castillo et al. 2020 custom POLE 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 · 19 not met · 0 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.6531+19G>T is an intronic variant located 19 base pairs downstream of POLE exon 46. It is not a null variant (nonsense, frameshift, or canonical splice site) and therefore does not meet PVS1 criteria (PMC6185798).
The variant is completely absent from all queried population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting PM2 at the supporting level.
SpliceAI predicts no significant splicing impact (max delta score = 0.02), meeting BP4 at the supporting benign level.
The León-Castillo et al. 2020 custom POLE framework, which customizes PM1, PS4, PP3, and BP4, applies exclusively to exonuclease-domain missense variants represented in its supplementary tables. This intronic variant is absent from those tables and none of the custom criterion specifications are triggered.
The variant is absent from ClinVar and COSMIC, and no functional studies, case reports, de novo events, or segregation data have been identified for this variant.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the overall evidence is equivocal. The criteria do not reach the threshold for Likely Pathogenic, Pathogenic, Likely Benign, or Benign classification. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_006231.4:c.6531+19G>T is completely absent from all queried population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP criteria, complete absence from large population cohorts supports PM2 at the supporting level. Note that coverage of deep intronic variants in exome-based datasets may be incomplete, but absence across both exome and genome resources is consistent with a very rare variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes
- AF = null)
- Absent from gnomAD v4.1 (exomes + genomes
- Absent from gnomAD-Canada v1.0 (HostSeq genomes
- AF = 0.0)
Still missing
- Deep intronic coverage in exome data may be limited
- genome-level confirmation is preferred
Sources
BP4 SupportingSpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.02, where DS_AG=0.0, DS_AL=0.0, DS_DG=0.0, DS_DL=0.02; all well below the 0.10 threshold). While BP4 typically requires multiple lines of computational evidence, SpliceAI is the primary and most relevant computational tool for assessing intronic variants near splice junctions, and its prediction supports no functional impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02 — no predicted donor gain
- acceptor gain
- donor loss
- or acceptor loss
Still missing
- Only single splice prediction tool available
- confirmatory tools (e.g.
- SpliceSiteFinder-like
- MaxEntScan) could strengthen assessment
Sources
Not met · 19 · evaluated, threshold not reached
PVS1 NM_006231.4:c.6531+19G>T is an intronic variant located 19 base pairs downstream of exon 46. It is not a nonsense, frameshift, or canonical ±1,2 splice consensus variant, and therefore does not trigger PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798). The generic PVS1 framework is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant class is intronic (+19)
- not a predicted null variant
- ClinGen SVI PVS1 framework (PMC6185798) does not apply to non-canonical intronic variants
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS2 No de novo evidence identified. No publications report this variant, and no de novo occurrence data are available. Details ▾Hide ▴
Still missing
- No trio or de novo sequencing data available for this variant
PS3 No functional studies identified for NM_006231.4:c.6531+19G>T. No experimental data testing this variant or a systematically characterized range including it were found in the literature or evidence sources. The León-Castillo et al. 2020 VCEP framework and its supplementary materials focus on exonuclease-domain missense variants and do not include functional data for this intronic variant. Details ▾Hide ▴
Still missing
- No in vitro or in vivo functional studies available for this intronic variant
PS4 Variant is absent from ClinVar and COSMIC. The León-Castillo et al. 2020 custom PS4 framework applies only to exact missense variants recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined EC count ≥10; this intronic variant does not meet those criteria. No germline case-control enrichment data are available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- Absent from COSMIC somatic database
- Custom PS4 framework not applicable (intronic
- not missense)
Still missing
- No case-control studies examining this variant
Sources
PM1 The León-Castillo et al. 2020 custom PM1 framework applies exclusively to specific exonuclease-domain missense variants listed in its evidence tables. NM_006231.4:c.6531+19G>T is an intronic variant and is not among the established hotspot or recurrent exonuclease-domain missense substitutions. It is not present in Supplementary Tables S1, S2, or S3. The variant is not located in a known mutational hotspot or critical functional domain that would satisfy generic PM1 criteria. Details ▾Hide ▴
Evidence considered
- Intronic variant (+19)
- not a missense variant in the exonuclease domain
- Not listed in León-Castillo et al. 2020 Supplementary Table S1 (recurrent variants)
- Custom PM1 framework rules require exact missense match to defined hotspot lists
Sources
vcep_path_250_323vcep_path_250_323_s002
PM6 No de novo evidence identified. No publications report this variant in a de novo context, and no trio-based sequencing data are available. Details ▾Hide ▴
Still missing
- No de novo occurrence data available
PP1 No segregation data available. No family studies or cosegregation analyses including this variant have been reported. Details ▾Hide ▴
Still missing
- No family-based cosegregation data available
PP2 PP2 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.6531+19G>T is an intronic variant, not a missense substitution, and does not meet this criterion. Details ▾Hide ▴
No further detail was recorded.
PP3 SpliceAI predicts no significant splicing impact for this variant (max delta score = 0.02), well below the standard 0.10 threshold for splice-altering variants. REVEL and BayesDel scores are not available for this intronic variant. The León-Castillo et al. 2020 custom PP3 framework applies only to missense variants represented in Supplementary Tables S2 or S3; this variant is absent from those tables. Under generic in silico assessment, the available computational evidence does not support a deleterious effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.02) — no predicted splicing alteration
- REVEL not available (intronic variant)
- BayesDel not available (intronic variant)
- Custom PP3 framework not applicable (variant absent from supplementary in silico tables)
Still missing
- No additional splicing prediction tools assessed beyond SpliceAI
Sources
PP4 No phenotype specificity data available. No clinical information or case-level phenotype data accompanied this variant to support that the patient's phenotype is specific for POLE-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
PP5 NM_006231.4:c.6531+19G>T is absent from ClinVar. No reputable source has reported this variant as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no classification by any submitter
Sources
BA1 NM_006231.4:c.6531+19G>T is absent from gnomAD. BA1 requires an allele frequency >1% in a population database, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (AF = 0
- well below the 1% BA1 threshold)
Sources
BS1 NM_006231.4:c.6531+19G>T is absent from all population databases. BS1 requires an allele frequency >0.3% in a population database, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (AF = 0
- well below the 0.3% BS1 threshold)
Sources
BS2 The variant has not been observed in any individual in population databases, so there is no evidence of observation in healthy adults. BS2 cannot be met without actual observations in healthy individuals. Details ▾Hide ▴
Still missing
- No observations in healthy adult individuals to support BS2
BS3 No functional studies demonstrating a benign effect for NM_006231.4:c.6531+19G>T have been identified. No experimental data are available to assess whether this intronic variant has no deleterious impact on gene function. Details ▾Hide ▴
Still missing
- No functional characterization of this intronic variant
BS4 No segregation data available to assess lack of cosegregation with disease. No family studies including this variant have been reported. Details ▾Hide ▴
Still missing
- No segregation data to evaluate disease cosegregation
BP2 No evidence of this variant observed in trans with a known pathogenic POLE variant. BP2 requires documented co-occurrence in trans with a pathogenic variant in a recessive disorder or in cis with a pathogenic variant in a dominant disorder. Details ▾Hide ▴
Still missing
- No phase-resolved observations with other POLE variants
BP5 No observation of this variant in a case where an alternate molecular basis for disease was identified. No clinical case data are available for this assessment. Details ▾Hide ▴
Still missing
- No clinical case data to assess alternate molecular cause
BP6 NM_006231.4:c.6531+19G>T is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no classification by any submitter
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AIntronic variant; no protein-level amino acid change to compare with an established pathogenic missense change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AIntronic variant with no predicted protein change. PM5 requires a different amino acid change at the same residue as a known pathogenic missense variant; this variant does not alter a protein residue. 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.6531+19G>T is an intronic variant, not a missense substitution; BP1 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) exonic variants where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_006231.4:c.6531+19G>T is an intronic variant, not a synonymous exonic substitution; BP7 does not apply. Details ▾Hide ▴
No further detail was recorded.
PS5 N/AVariant is absent from ClinVar; no established pathogenic variant at the same nucleotide position has been reported by a reputable source. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.6531+19G>T
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132626098 C>A
- GRCh37
- chr12:133202684 C>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
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
BP4 SupportingSpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.02, where DS_AG=0.0, DS_AL=0.0, DS_DG=0.0, DS_DL=0.02; all well below the 0.10 threshold). While BP4 typically requires multiple lines of computational evidence, SpliceAI is the primary and most relevant computational tool for assessing intronic variants near splice junctions, and its prediction supports no functional impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02 — no predicted donor gain
- acceptor gain
- donor loss
- or acceptor loss
Still missing
- Only single splice prediction tool available
- confirmatory tools (e.g.
- SpliceSiteFinder-like
- MaxEntScan) could strengthen assessment
Sources
PP3 SpliceAI predicts no significant splicing impact for this variant (max delta score = 0.02), well below the standard 0.10 threshold for splice-altering variants. REVEL and BayesDel scores are not available for this intronic variant. The León-Castillo et al. 2020 custom PP3 framework applies only to missense variants represented in Supplementary Tables S2 or S3; this variant is absent from those tables. Under generic in silico assessment, the available computational evidence does not support a deleterious effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.02 (DS_AG=0.0
- DS_AL=0.0
- DS_DG=0.0
- DS_DL=0.02) — no predicted splicing alteration
- REVEL not available (intronic variant)
- BayesDel not available (intronic variant)
- Custom PP3 framework not applicable (variant absent from supplementary in silico tables)
Still missing
- No additional splicing prediction tools assessed beyond SpliceAI
Sources
BP7 N/ABP7 applies to synonymous (silent) exonic variants where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_006231.4:c.6531+19G>T is an intronic variant, not a synonymous exonic substitution; BP7 does not apply. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 0.020
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.6531%2B19G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133202684-C-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132626098-C-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132626098-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.6531…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.6531+19G%3ET
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 = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).