About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.6531+4C>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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
Invitae (Labcorp Genetics), a reputable clinical testing laboratory, reports this variant as Likely benign with criteria provided in ClinVar (SCV000772749, review status: criteria provided, single submitter). Under generic ACMG/AMP, a reputable source reporting the variant as benign supports BP6 at the Supporting level.
Recorded classification: Uncertain significance
Only one criterion met: BP6 (supporting benign) based on Invitae ClinVar submission reporting Likely benign. No pathogenic criteria are met. Under the León-Castillo et al. 2020 custom POLE framework (which mirrors ACMG/AMP 2015 final combination rules), a single supporting benign criterion is insufficient for Likely Benign (requires ≥2 Supporting benign or 1 Strong benign + 1 Supporting benign). The variant defaults to Variant of Uncertain Significance (VUS).
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
28 / 1,589,258 alleles
gnomAD v4.1: 28 / 1,589,258 alleles. Recorded AF 1.76183e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.2551e-05; MAF= 0.00326%, 8/245768 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000152161; MAF= 0.01522%, 1/6572 alleles, homozygotes = 0); grpmax FAF= 2.658e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.130 maximum delta
Recorded SpliceAI maximum delta score: 0.130. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Likely benign · 1 Uncertain significance.
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV114455520, n = 2 times).
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.
29 criteria with recorded statuses: 1 met · 9 not met · 9 not assessed · 10 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+4C>T is an intronic variant at position +4 of intron 46 in POLE. SpliceAI predicts no significant splicing impact (max delta score 0.13).
This variant is present in gnomAD at extremely low frequency (v2.1: 8/245,768 alleles, AF=3.26e-05; v4.1: 28/1,589,258 alleles, AF=1.76e-05). The frequency does not reach BA1 (>1%) or BS1 (>0.3%) thresholds.
Invitae (Labcorp Genetics) reports this variant as Likely benign with criteria provided in ClinVar (SCV000772749). Ambry Genetics reports it as Uncertain significance (SCV000671346). Both are single-submitter clinical testing classifications without expert panel review.
The only criterion met is BP6 (Supporting benign) based on the Invitae ClinVar submission reporting Likely benign. No pathogenic criteria are met. Under ACMG/AMP 2015 combination rules, a single Supporting benign criterion is insufficient for a Likely benign classification (requires ≥2 Supporting benign or 1 Strong benign + 1 Supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
BP6 SupportingInvitae (Labcorp Genetics), a reputable clinical testing laboratory, reports this variant as Likely benign with criteria provided in ClinVar (SCV000772749, review status: criteria provided, single submitter). Under generic ACMG/AMP, a reputable source reporting the variant as benign supports BP6 at the Supporting level. Details ▾Hide ▴
Evidence considered
- ClinVar SCV000772749: Likely benign from Invitae (Labcorp Genetics)
- criteria provided
- Reputable clinical laboratory with criteria-based assessment
Sources
Not met · 9 · evaluated, threshold not reached
PVS1 Intronic variant at c.6531+4 (intron 46), outside the canonical ±1,2 splice consensus. SpliceAI predicts no significant splicing impact (max delta score 0.13). Does not meet ClinGen SVI PVS1 null-variant criteria (PMC6185798). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.13 — no significant splice impact
- Variant is at +4 position
- not canonical ±1
- 2 splice site
- ClinGen SVI PVS1 framework does not classify this as a null-variant bucket
Sources
PS4 Two single-submitter ClinVar entries (Likely benign from Invitae, Uncertain significance from Ambry) do not constitute significantly increased prevalence in affected individuals. The custom POLE PS4 rule (León-Castillo et al. 2020) applies only to recurrent exonuclease-domain missense variants; this intronic variant does not qualify. No published case-control data are available. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign (Invitae
- 1 submitter)
- Uncertain significance (Ambry
- Custom POLE PS4 rule is limited to missense variants in COSMIC/TCGA EC cohorts
- No case-control studies identified
Still missing
- No case-control data
- No published case reports with this variant
Sources
PM2 Variant is present in gnomAD at extremely low frequency (v2.1: 8/245,768 alleles, AF=3.26e-05; v4.1: 28/1,589,258 alleles, AF=1.76e-05) and SpliceAI predicts no splicing impact. The presence in population databases, combined with absence of predicted functional consequence, does not support PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 8 alleles
- AF=3.26e-05 (0.003%)
- gnomAD v4.1: 28 alleles
- AF=1.76e-05 (0.002%)
- SpliceAI max delta 0.13 — no predicted effect
Sources
PP3 SpliceAI predicts no significant splicing impact (max delta 0.13). REVEL and BayesDel scores are not available for this intronic variant. The custom POLE PP3 rule (León-Castillo et al. 2020) applies only to missense variants in Supplementary Tables S2/S3; this variant is not present in those tables. No computational tools predict a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.13 — no splicing impact
- REVEL and BayesDel not applicable to intronic variant
- Variant absent from Supplementary Tables S2 and S3
Sources
PP4 No patient phenotype or family history data are available to assess whether the phenotype is highly specific for a POLE-related disorder. Details ▾Hide ▴
Still missing
- No clinical phenotype data available
PP5 ClinVar reports this variant as Likely benign (Invitae, 1 submitter) and Uncertain significance (Ambry, 1 submitter). No reputable source has reported this variant as pathogenic. The cited PMID 25394175 (Hampel et al. 2015) is a general guideline for cancer predisposition referral and does not mention this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign (Invitae) and VUS (Ambry) — not pathogenic
- PMID 25394175 reviewed
- general guideline
- variant not mentioned
Sources
BA1 gnomAD v2.1 allele frequency = 3.26e-05 (0.003%) and gnomAD v4.1 = 1.76e-05 (0.002%), both well below the 1% BA1 threshold for a dominant disorder. Details ▾Hide ▴
BS1 The variant frequency (gnomAD v2.1 AF=3.26e-05, 0.003%; v4.1 AF=1.76e-05, 0.002%) is well below the 0.3% BS1 threshold. The frequency is not greater than expected for a POLE-related disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.003% — below 0.3% threshold
- gnomAD v4.1 AF=0.002% — below 0.3% threshold
Sources
BP4 SpliceAI predicts no significant splicing impact (max delta 0.13), but this constitutes only a single line of computational evidence. REVEL and BayesDel scores are not available for this intronic variant. The custom POLE BP4 rule applies only to missense variants in Supplementary Tables S2/S3; this variant is not present in those tables. Multiple lines of computational evidence are not available to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.13 — single line only
- REVEL and BayesDel not available for intronic variant
- Variant absent from Supplementary Tables S2 and S3
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
- No de novo studies identified
PM6 No de novo data available for this variant. Details ▾Hide ▴
Still missing
- No de novo studies identified
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
- No segregation studies identified
BS2 No data on observation of this variant in healthy adult individuals for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy adult carrier data
BS3 No well-established in vitro or in vivo functional studies are available for this variant. SpliceAI prediction alone does not constitute a functional study. Details ▾Hide ▴
Still missing
- No functional studies available
BS4 No segregation data available to evaluate lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No segregation data
BP2 No data on observation of this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
- No phase data with pathogenic variants
BP5 No data on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data
PS5 No validated de novo data available for this variant. Details ▾Hide ▴
Still missing
- No de novo studies identified
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AIntronic variant with no amino acid change; PS1 requires a different nucleotide change at the same codon producing the same missense as an established pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PS3 N/AIntronic variant with no predicted protein change (NP_006222.2:p.?); SpliceAI predicts no significant splicing impact. No functional studies are relevant for a variant with no predicted molecular consequence. Details ▾Hide ▴
Sources
PM1 N/AThe custom POLE PM1 rules (León-Castillo et al. 2020) apply only to exonuclease-domain missense variants. This intronic variant at c.6531+4 is not located in the exonuclease domain (residues 268–471) and is not a missense change. Details ▾Hide ▴
Evidence considered
- León-Castillo PM1 rules restricted to missense exonuclease-domain hotspots and recurrent variants
- Variant not listed in Supplementary Table S1
Sources
vcep_path_250_323vcep_path_250_323_s002
PM3 N/APOLE is not associated with a recessive disorder; PM3 requires recessive disease context. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a substitution, not a protein-length altering change (in-frame deletion/insertion, stop-loss, or initiation codon). Details ▾Hide ▴
No further detail was recorded.
PM5 N/AIntronic variant with no amino acid change; PM5 requires a different missense change at the same residue as a known pathogenic missense variant. Details ▾Hide ▴
No further detail was recorded.
PP2 N/AIntronic variant, not a missense change. PP2 is specific to missense variants in genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AIntronic variant, not a missense change. BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a substitution, not an in-frame deletion or insertion. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is specific to synonymous (silent) exonic variants for which splicing algorithms predict no impact and the nucleotide is not highly conserved. This variant is an intronic substitution at c.6531+4, not a synonymous coding variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.6531+4C>T
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132626113 G>A
- GRCh37
- chr12:133202699 G>A
- ClinVar
- 484442, 2366079
- COSMIC
- COSV114455520
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
28 / 1,589,258 alleles
AF 1.76e-05 · 0 homozygotes · FAF 1.76e-05
gnomAD v2.1
8 / 245,768 alleles
AF 3.26e-05 · 0 homozygotes · FAF 2.66e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.8e-05 · 28 / 1,589,258 alleles · 0 hom · FAF 1.8e-05
| African/African American4 / 74,160 | 5.4e-05 |
| Admixed American2 / 56,284 | 3.6e-05 |
| South Asian3 / 87,992 | 3.4e-05 |
| Remaining individuals1 / 61,522 | 1.6e-05 |
| European (non-Finnish)18 / 1,168,500 | 1.5e-05 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 3.3e-05 · 8 / 245,768 alleles · 0 hom · FAF 2.7e-05
| Remaining individuals1 / 6,572 | 0.00015 |
| African/African American3 / 21,606 | 0.00014 |
| Admixed American2 / 31,362 | 6.4e-05 |
| European (non-Finnish)2 / 109,636 | 1.8e-05 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.76183e-05; MAF= 0.00176%, 28/1589258 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.39374e-05; MAF= 0.00539%, 4/74160 alleles, homozygotes = 0); grpmax FAF= 1.759e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.2551e-05; MAF= 0.00326%, 8/245768 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000152161; MAF= 0.01522%, 1/6572 alleles, homozygotes = 0); grpmax FAF= 2.658e-05.
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 SpliceAI predicts no significant splicing impact (max delta 0.13). REVEL and BayesDel scores are not available for this intronic variant. The custom POLE PP3 rule (León-Castillo et al. 2020) applies only to missense variants in Supplementary Tables S2/S3; this variant is not present in those tables. No computational tools predict a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.13 — no splicing impact
- REVEL and BayesDel not applicable to intronic variant
- Variant absent from Supplementary Tables S2 and S3
Sources
BP4 SpliceAI predicts no significant splicing impact (max delta 0.13), but this constitutes only a single line of computational evidence. REVEL and BayesDel scores are not available for this intronic variant. The custom POLE BP4 rule applies only to missense variants in Supplementary Tables S2/S3; this variant is not present in those tables. Multiple lines of computational evidence are not available to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.13 — single line only
- REVEL and BayesDel not available for intronic variant
- Variant absent from Supplementary Tables S2 and S3
Sources
BP7 N/ABP7 is specific to synonymous (silent) exonic variants for which splicing algorithms predict no impact and the nucleotide is not highly conserved. This variant is an intronic substitution at c.6531+4, not a synonymous coding variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. This is a general clinical practice guideline and does not report or evaluate individual variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of the ACMG-AMP variant classification criteria. This is a methodology paper describing a variant classification framework and does not report or evaluate individual POLE variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
28 / 1,589,258 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.130
Open source ↗
ClinVar
1 Likely benign · 1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/484442/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133202699-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132626113-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132626113-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.6531…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126832545
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= 1.76183e-05; MAF= 0.00176%, 28/1589258 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.39374e-05; MAF= 0.00539%, 4/74160 alleles, homozygotes = 0); grpmax FAF= 1.759e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.2551e-05; MAF= 0.00326%, 8/245768 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000152161; MAF= 0.01522%, 1/6572 alleles, homozygotes = 0); grpmax FAF= 2.658e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 484442)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV114455520, n = 2 times).