About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.2561+21G>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: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
No ACMG/AMP pathogenic or benign criteria are met for NM_006231.4:c.2561+21G>A. All evaluated criteria returned 'not_met' or 'not_applicable'. The León-Castillo 2020 custom POLE framework applies exclusively to missense variants, and this intronic variant falls outside its scope. Per ACMG/AMP 2015 default, when no criteria of any strength are satisfied the variant is classified as a 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
51 / 1,607,222 alleles
gnomAD v4.1: 51 / 1,607,222 alleles. Recorded AF 3.17318e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.50617e-05; MAF= 0.00851%, 24/282148 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000415973; MAF= 0.04160%, 3/7212 alleles, homozygotes = 0); grpmax FAF= 9.376e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016299032924046506, 3/18406 alleles, homozygotes = 0).
No listed criterion applied
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV114455825, n = 1 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: 0 met · 21 not met · 0 not assessed · 8 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.2561+21G>A is an intronic variant in POLE located 21 bases into intron 22.
SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a functionally silent intronic change.
The variant is rare in population databases (gnomAD v2.1 AF = 0.0085%, 24/282,148 alleles; v4.1 AF = 0.0032%, 51/1,607,222 alleles), but rarity is expected for functionally silent intronic variants and is not informative for pathogenicity.
The variant is absent from ClinVar; no germline clinical classification is available.
It has been observed once as a somatic event in COSMIC (COSV114455825), which does not inform germline pathogenicity.
The León-Castillo 2020 custom POLE framework applies exclusively to missense variants; this intronic variant falls outside its scope.
No functional, segregation, de novo, case-control, or phenotypic data exist for this variant.
No ACMG/AMP pathogenic or benign criteria are met; the variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Not met · 21 · evaluated, threshold not reached
PS1 No previously classified pathogenic variant at nucleotide position c.2561+21 is reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant or any alternate change at c.2561+21
Sources
PS2 No de novo observation data are available for this variant. Details ▾Hide ▴
Still missing
- No trio or de novo testing data
PS3 No functional studies have characterized this intronic variant. No experimental data exist for c.2561+21G>A or a systematically characterized range that includes this position. Details ▾Hide ▴
Still missing
- No functional characterization of this intronic variant
PS4 The León-Castillo 2020 custom POLE framework restricts PS4 to exact missense variants recurrent in COSMIC and TCGA endometrial carcinoma cohorts with combined EC count ≥10. This is an intronic variant with no protein change and is absent from the supplementary recurrence table. No germline case-control enrichment data exist. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not a missense variant in León-Castillo supplementary tables
Still missing
- No case-control studies
Sources
vcep_path_250_323_s002vcep_path_250_323
PM1 The León-Castillo 2020 custom POLE PM1 framework applies only to exact exonuclease-domain missense substitutions. This is an intronic variant located 21 bases into intron 22, outside the exonuclease domain and not in any established mutational hotspot or critical functional domain. The variant is also absent from the supplementary hotspot tables. Details ▾Hide ▴
Evidence considered
- Intronic variant outside exonuclease domain
- not a missense substitution in León-Castillo hotspot list
Sources
vcep_path_250_323_s002vcep_path_250_323
PM2 Although the variant is rare in population databases (gnomAD v2.1 AF = 0.0085%, 24/282,148 alleles; v4.1 AF = 0.0032%, 51/1,607,222 alleles), rarity of a deep intronic variant with no predicted functional consequence (SpliceAI delta = 0.00) is expected of most intronic polymorphisms and is not informative for pathogenicity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.0085% (24/282
- 148)
- gnomAD v4.1 AF = 0.0032% (51/1
- 607
- 222)
- SpliceAI max delta = 0.00
Sources
PM6 No de novo observation data are available for this variant. Details ▾Hide ▴
Still missing
- No trio or de novo testing data
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data
PP3 SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel scores are unavailable for this non-coding variant. No computational evidence supports a deleterious effect. The León-Castillo custom PP3 framework applies only to missense variants in the supplementary in silico tables. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- Variant absent from León-Castillo in silico tables (S2
- S3)
Sources
PP4 No proband phenotype or clinical specificity data are available to assess whether the variant is in an individual with a phenotype specific for POLE-related disease. Details ▾Hide ▴
Still missing
- No clinical phenotype information provided
PP5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic. Details ▾Hide ▴
BA1 Global allele frequency in gnomAD v2.1 is 0.0085% (24/282,148 alleles), far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 Global allele frequency in gnomAD v2.1 is 0.0085%, far below the 0.3% BS1 threshold. Details ▾Hide ▴
BS2 No confirmed observation in a healthy adult individual with full penetrance POLE-related disorder phenotype data is available. Presence in gnomAD population cohorts does not alone satisfy BS2 without disease-phenotype exclusion data. Details ▾Hide ▴
Still missing
- No healthy adult control data with phenotype confirmation
BS3 No functional studies demonstrating a neutral or benign effect exist for this variant. Details ▾Hide ▴
Still missing
- No functional characterization available
BS4 No segregation data are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data
BP2 No observation of this variant in trans with a known pathogenic POLE variant has been reported. Details ▾Hide ▴
Still missing
- No phase data with pathogenic variants
BP4 SpliceAI predicts no splicing impact (max delta = 0.00), but BP4 requires multiple lines of computational evidence suggesting no impact. Only one predictor (SpliceAI) is available for this non-coding variant; REVEL and BayesDel do not apply to intronic variants. The León-Castillo custom BP4 framework applies only to missense variants in the supplementary tables. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- Single predictor only
- multiple lines not available for non-coding variant
Sources
BP5 No evidence of an alternate molecular basis for disease has been identified in this case. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴
PS5 No alternate pathogenic variant at position c.2561+21 has been identified in ClinVar or the literature. Details ▾Hide ▴
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant at c.2561+21 position, 21 bases into intron 22, with no predicted splicing impact (SpliceAI max delta = 0.00). Does not meet null-variant criteria (nonsense, frameshift, canonical ±1/2 splice) per ClinGen PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splice impact (delta = 0.00)
- Variant is deep intronic (+21)
- outside canonical splice consensus
Sources
PM3 N/APM3 applies to recessive disorders; POLE-associated disorders follow autosomal dominant inheritance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length changes (stop-loss, in-frame del/ins); this is an intronic substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AIntronic variant with no protein change (p.?); PM5 requires a same-residue missense comparator with a different pathogenic amino acid change. Details ▾Hide ▴
Evidence considered
- No protein consequence
- intronic variant
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with low benign missense variation. This is an intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is an intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) coding variants. This is an intronic variant, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.2561+21G>A
- Protein (HGVS p.)
- NP_006222.2:p.?
- GRCh38
- chr12:132664349 C>T
- GRCh37
- chr12:133240935 C>T
- COSMIC
- COSV114455825
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
51 / 1,607,222 alleles
AF 3.17e-05 · 0 homozygotes · FAF 0.000128
gnomAD v2.1
24 / 282,148 alleles
AF 8.51e-05 · 0 homozygotes · FAF 9.38e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.2e-05 · 51 / 1,607,222 alleles · 0 hom · FAF 0.00013
| Admixed American13 / 59,970 | 0.00022 |
| African/African American9 / 74,758 | 0.00012 |
| Remaining individuals6 / 62,266 | 9.6e-05 |
| South Asian7 / 90,954 | 7.7e-05 |
| European (Finnish)2 / 63,388 | 3.2e-05 |
| European (non-Finnish)14 / 1,174,468 | 1.2e-05 |
0 alternate alleles recorded in 4 other groups: Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 8.5e-05 · 24 / 282,148 alleles · 0 hom · FAF 9.4e-05
| Remaining individuals3 / 7,212 | 0.00042 |
| African/African American6 / 24,956 | 0.00024 |
| Admixed American6 / 35,424 | 0.00017 |
| South Asian5 / 30,614 | 0.00016 |
| East Asian1 / 19,952 | 5e-05 |
| European (non-Finnish)3 / 128,966 | 2.3e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.17318e-05; MAF= 0.00317%, 51/1607222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000216775; MAF= 0.02168%, 13/59970 alleles, homozygotes = 0); grpmax FAF= 0.00012751.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.50617e-05; MAF= 0.00851%, 24/282148 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000415973; MAF= 0.04160%, 3/7212 alleles, homozygotes = 0); grpmax FAF= 9.376e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016299032924046506, 3/18406 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel scores are unavailable for this non-coding variant. No computational evidence supports a deleterious effect. The León-Castillo custom PP3 framework applies only to missense variants in the supplementary in silico tables. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- Variant absent from León-Castillo in silico tables (S2
- S3)
Sources
BP4 SpliceAI predicts no splicing impact (max delta = 0.00), but BP4 requires multiple lines of computational evidence suggesting no impact. Only one predictor (SpliceAI) is available for this non-coding variant; REVEL and BayesDel do not apply to intronic variants. The León-Castillo custom BP4 framework applies only to missense variants in the supplementary tables. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00
- Single predictor only
- multiple lines not available for non-coding variant
Sources
BP7 N/ABP7 applies to synonymous (silent) coding variants. This is an intronic variant, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
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
51 / 1,607,222 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.2561%2B21G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133240935-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132664349-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132664349-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.2561…
- OncoKB ↗www.oncokb.org/gene/POLE/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126837876
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= 3.17318e-05; MAF= 0.00317%, 51/1607222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000216775; MAF= 0.02168%, 13/59970 alleles, homozygotes = 0); grpmax FAF= 0.00012751.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.50617e-05; MAF= 0.00851%, 24/282148 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000415973; MAF= 0.04160%, 3/7212 alleles, homozygotes = 0); grpmax FAF= 9.376e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016299032924046506, 3/18406 alleles, homozygotes = 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 previously been reported in somatic cancers (COSMIC; COSV114455825, n = 1 times).