About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.2468+16_2468+21dup, 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
This variant is absent from ClinVar and present in gnomAD at very low allele frequency: v2.1 AF = 7.82 × 10⁻⁵ (22/281,506 alleles) and v4.1 AF = 7.90 × 10⁻⁵ (127/1,608,390 alleles). Both frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment. No homozygotes observed. PM2 is met at supporting strength.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no splicing impact for this intronic duplication (max delta score = 0.02, well below the 0.10 threshold). The variant lies at positions +16 to +21, outside the splice consensus region. The most pertinent computational tool for an intronic variant shows no evidence of altered splicing. REVEL and BayesDel are not applicable (not an SNV). BP4 is met at supporting strength based on SpliceAI prediction of no splicing impact.
Recorded classification: Uncertain significance
The León-Castillo et al. 2020 custom POLE framework provides standard ACMG/AMP 2015 final combination rules. Only two criteria are met: PM2 at supporting strength (pathogenic) and BP4 at supporting strength (benign). This combination of one pathogenic supporting and one benign supporting criterion satisfies no pathogenic, likely pathogenic, benign, or likely benign rule in the framework. The conflicting evidence defaults to VUS per ACMG/AMP 2015.
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
127 / 1,608,390 alleles
gnomAD v4.1: 127 / 1,608,390 alleles. Recorded AF 7.89609e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.81511e-05; MAF= 0.00782%, 22/281506 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277855; MAF= 0.02779%, 2/7198 alleles, homozygotes = 0); grpmax FAF= 5.709e-05.
gnomAD-Canada
Not available in 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.
29 criteria with recorded statuses: 2 met · 5 not met · 12 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.2468+16_2468+21dup is an intronic duplication in intron 21 of POLE, located at positions +16 to +21 downstream of exon 21.
This variant is absent from ClinVar and has not been reported in COSMIC or the published literature in association with disease.
The variant is present in gnomAD at very low frequency (v2.1 AF = 0.0078%, v4.1 AF = 0.0079%) with no homozygotes observed, meeting PM2 at supporting strength.
SpliceAI predicts no splicing impact (max delta = 0.02), meeting BP4 at supporting strength.
The custom POLE framework criteria (PM1, PS4, PP3, BP4 via León-Castillo et al. 2020) are missense-specific and do not apply to this intronic duplication.
PVS1 is not applicable as the variant is outside the canonical splice consensus and does not meet null-variant criteria per ClinGen PVS1 framework.
With only PM2_Supporting and BP4_Supporting applied, evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a variant of uncertain significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from ClinVar and present in gnomAD at very low allele frequency: v2.1 AF = 7.82 × 10⁻⁵ (22/281,506 alleles) and v4.1 AF = 7.90 × 10⁻⁵ (127/1,608,390 alleles). Both frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment. No homozygotes observed. PM2 is met at supporting strength. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.0078% (22/281
- 506 alleles
- 0 homozygotes)
- gnomAD v4.1: AF = 0.0079% (127/1
- 608
- 390 alleles
- Absent from ClinVar
Sources
BP4 SupportingSpliceAI predicts no splicing impact for this intronic duplication (max delta score = 0.02, well below the 0.10 threshold). The variant lies at positions +16 to +21, outside the splice consensus region. The most pertinent computational tool for an intronic variant shows no evidence of altered splicing. REVEL and BayesDel are not applicable (not an SNV). BP4 is met at supporting strength based on SpliceAI prediction of no splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no splicing impact predicted at acceptor or donor sites)
- SpliceAI scores: acceptor_gain=0.02
- all other delta scores <0.01
Still missing
- No additional in silico tools applicable (REVEL/BayesDel unavailable for non-SNV)
Sources
Not met · 5 · evaluated, threshold not reached
PS4 The variant is absent from ClinVar and COSMIC. The custom POLE PS4 rule (from León-Castillo et al. 2020) requires an exact missense variant recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined EC count ≥10; this intronic duplication does not meet the missense prerequisite and is not listed in the supplementary tables. Under generic ACMG/AMP 2015, no case-control data are available. PS4 is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- Not present in COSMIC
- Not listed in León-Castillo Supplementary Table S1
Still missing
- No case-control or cohort data for this variant
Sources
clinvar ↗vcep_path_250_323_s002
PM1 The custom POLE PM1 rules (from León-Castillo et al. 2020) apply exclusively to specific missense variants in the exonuclease domain. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication in intron 21, outside the exonuclease domain and not a missense variant. Under generic ACMG/AMP 2015, the variant does not lie within a well-established mutational hotspot or critical functional domain. The variant is absent from the León-Castillo supplementary tables. PM1 is not met. Details ▾Hide ▴
Evidence considered
- Intronic duplication outside exonuclease domain
- Not listed among established hotspot mutations in León-Castillo et al. 2020
- Not recurrent in COSMIC or TCGA EC cohorts
Sources
vcep_path_250_323vcep_path_250_323_s002
PP3 The custom POLE PP3 rule requires an exact missense variant in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This intronic duplication is not a missense variant and does not appear in the León-Castillo supplementary tables. Under generic ACMG/AMP 2015: REVEL and BayesDel are unavailable (not an SNV), HCI prior does not support POLE, and SpliceAI predicts no splicing impact (max delta = 0.02). No computational evidence supports a deleterious effect. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no splicing impact predicted)
- REVEL not available (not SNV)
- Not listed in León-Castillo Supplementary Tables S2 or S3
Sources
BA1 gnomAD allele frequency is well below the 1% BA1 threshold. v2.1 AF = 0.0078%, v4.1 AF = 0.0079%. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.0078% (<1% threshold)
- gnomAD v4.1 AF = 0.0079% (<1% threshold)
Sources
BS1 gnomAD allele frequency is below the 0.3% BS1 threshold. v2.1 AF = 0.0078%, v4.1 AF = 0.0079%. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.0078% (<0.3% threshold)
- gnomAD v4.1 AF = 0.0079% (<0.3% threshold)
Sources
Not assessed · 12 · no assessment recorded
PS2 No de novo data available for this variant. No publications report parent-of-origin testing for NM_006231.4:c.2468+16_2468+21dup. Details ▾Hide ▴
Still missing
- No de novo observations in the literature for this variant
PS3 No functional studies available for this intronic duplication. No publications report in vitro or in vivo functional assessment of NM_006231.4:c.2468+16_2468+21dup. Details ▾Hide ▴
Still missing
- No functional studies identified for this variant
PM6 No de novo data available. No publications report a confirmed de novo occurrence of NM_006231.4:c.2468+16_2468+21dup with maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo observations reported for this variant
PP1 No segregation data available. No family studies have been reported for NM_006231.4:c.2468+16_2468+21dup. Details ▾Hide ▴
Still missing
- No cosegregation data available
PP4 No phenotype or family history data are available for individuals carrying NM_006231.4:c.2468+16_2468+21dup. PP4 requires that the variant phenotype is highly specific for the disease. Details ▾Hide ▴
Still missing
- No phenotype data available for variant carriers
PP5 The variant is absent from ClinVar. No expert panel or reputable source has classified NM_006231.4:c.2468+16_2468+21dup. PP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
Still missing
- No reputable source classification available
BS2 BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder. No such data are available for NM_006231.4:c.2468+16_2468+21dup. Details ▾Hide ▴
Still missing
- No healthy adult carrier data available
BS3 No functional studies demonstrating no deleterious effect are available for this intronic duplication. Details ▾Hide ▴
Still missing
- No functional studies demonstrating benign effect
BS4 No segregation data are available. BS4 requires non-segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No cosegregation data available
BP2 No data on in cis observation with a known pathogenic variant in POLE are available for this variant. Details ▾Hide ▴
Still missing
- No information on in cis observation with pathogenic variant
BP6 No reputable source has classified NM_006231.4:c.2468+16_2468+21dup as benign. BP6 requires a reputable source classification as benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
Still missing
- No reputable source classification available
PS5 No reputable source has recently reported this variant as pathogenic. PS5 requires a reputable source classification where the evidence is not available for independent evaluation. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no expert panel classification available
Still missing
- No prior classification by a reputable source
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.2468+16_2468+21dup is an intronic duplication in intron 21 of POLE, located at positions +16 to +21 downstream of exon 21. This variant is outside the canonical splice consensus (±1,2) and does not fall into the ClinGen PVS1 null-variant buckets (nonsense, frameshift, or canonical splice). Per pvs1_variant_assessment, apply_generic_pvs1_framework is false and variant_bucket is 'other'. Details ▾Hide ▴
Evidence considered
- Intronic duplication outside canonical splice consensus
- not eligible for PVS1 under ClinGen PVS1 decision tree (PMC6185798)
Sources
PS1 N/ANo known pathogenic variant is reported at this intronic position with a different nucleotide change. PS1 requires a nucleotide change at the same position with a known pathogenic comparator. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator at the same intronic position identified in ClinVar or literature
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions in a nonrepeat region or stop-loss variants that alter protein length. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication that does not change protein length. Details ▾Hide ▴
Evidence considered
- Intronic duplication does not alter protein coding sequence or length
PM5 N/APM5 requires a different pathogenic amino acid change at the same residue. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication with no amino acid change (NP_006222.2:p.?). No same-residue comparator can be identified. Per pm5_candidates, eligible_for_classic_pm5_search is false. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no protein residue context available for PM5 comparison
Sources
pm5_candidates
PP2 N/APP2 is specific to missense variants in genes where missense is a common disease mechanism and benign missense variation is low. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication, not a missense variant. Details ▾Hide ▴
Evidence considered
- Not a missense variant
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is an intronic duplication, not a missense variant. Details ▾Hide ▴
Evidence considered
- Not a missense variant
BP3 N/ABP3 is specific to in-frame deletions/insertions in repetitive regions without a known function. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication, not an in-frame coding insertion/deletion. Details ▾Hide ▴
Evidence considered
- Intronic duplication
- not an in-frame coding variant
BP5 N/ABP5 requires that the variant is found in a case with a clear alternate molecular cause of disease. No such data are available for this variant, and no ClinVar entry exists to identify an alternate mechanism. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis for disease identified in association with this variant
BP7 N/ABP7 is specific to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication, not a synonymous coding variant. Per ACMG/AMP 2015 guidelines, BP7 applies only to synonymous variants. Details ▾Hide ▴
Evidence considered
- Intronic duplication
- not a synonymous coding variant
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.2468+16_2468+21dup
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132665280 T>TCCCGGG
- GRCh37
- chr12:133241866 T>TCCCGGG
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
127 / 1,608,390 alleles
AF 7.9e-05 · 0 homozygotes · FAF 0.000235
gnomAD v2.1
22 / 281,506 alleles
AF 7.82e-05 · 0 homozygotes · FAF 5.71e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 7.9e-05 · 127 / 1,608,390 alleles · 0 hom · FAF 0.00023
| Admixed American21 / 59,864 | 0.00035 |
| African/African American13 / 74,716 | 0.00017 |
| Remaining individuals10 / 62,242 | 0.00016 |
| European (non-Finnish)80 / 1,175,914 | 6.8e-05 |
| East Asian1 / 44,612 | 2.2e-05 |
| South Asian2 / 90,908 | 2.2e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 7.8e-05 · 22 / 281,506 alleles · 0 hom · FAF 5.7e-05
| Remaining individuals2 / 7,198 | 0.00028 |
| Admixed American5 / 35,350 | 0.00014 |
| African/African American3 / 24,922 | 0.00012 |
| European (non-Finnish)10 / 128,384 | 7.8e-05 |
| East Asian1 / 19,904 | 5e-05 |
| South Asian1 / 30,584 | 3.3e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.89609e-05; MAF= 0.00790%, 127/1608390 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000350795; MAF= 0.03508%, 21/59864 alleles, homozygotes = 0); grpmax FAF= 0.00023458.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.81511e-05; MAF= 0.00782%, 22/281506 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277855; MAF= 0.02779%, 2/7198 alleles, homozygotes = 0); grpmax FAF= 5.709e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splicing impact for this intronic duplication (max delta score = 0.02, well below the 0.10 threshold). The variant lies at positions +16 to +21, outside the splice consensus region. The most pertinent computational tool for an intronic variant shows no evidence of altered splicing. REVEL and BayesDel are not applicable (not an SNV). BP4 is met at supporting strength based on SpliceAI prediction of no splicing impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no splicing impact predicted at acceptor or donor sites)
- SpliceAI scores: acceptor_gain=0.02
- all other delta scores <0.01
Still missing
- No additional in silico tools applicable (REVEL/BayesDel unavailable for non-SNV)
Sources
PP3 The custom POLE PP3 rule requires an exact missense variant in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result. This intronic duplication is not a missense variant and does not appear in the León-Castillo supplementary tables. Under generic ACMG/AMP 2015: REVEL and BayesDel are unavailable (not an SNV), HCI prior does not support POLE, and SpliceAI predicts no splicing impact (max delta = 0.02). No computational evidence supports a deleterious effect. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no splicing impact predicted)
- REVEL not available (not SNV)
- Not listed in León-Castillo Supplementary Tables S2 or S3
Sources
BP7 N/ABP7 is specific to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_006231.4:c.2468+16_2468+21dup is an intronic duplication, not a synonymous coding variant. Per ACMG/AMP 2015 guidelines, BP7 applies only to synonymous variants. Details ▾Hide ▴
Evidence considered
- Intronic duplication
- not a synonymous coding variant
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
127 / 1,608,390 recorded alleles
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.2468%2B16_24…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133241866-T-TCCCGGG?datase…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132665280-T-TCCCGGG?dat…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132665280-T-TCCCGGG
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.2468…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.2468+16_2468+21dup
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= 7.89609e-05; MAF= 0.00790%, 127/1608390 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000350795; MAF= 0.03508%, 21/59864 alleles, homozygotes = 0); grpmax FAF= 0.00023458.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.81511e-05; MAF= 0.00782%, 22/281506 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000277855; MAF= 0.02779%, 2/7198 alleles, homozygotes = 0); grpmax FAF= 5.709e-05.
gnomAD-Canada
Not available in 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).