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POLEc.4952+9A>GUncertain significance
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Variant interpretation report

POLE c.4952+9A>G, p.?

NM_006231.4:c.4952+9A>G NP_006222.2:p.? View identifiers
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.

About POLE

No gene-level summary was recorded for this case.

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 gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals), which is below the project's PM2 threshold of 0.1% and supports rarity in the general population.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Computational splicing prediction supports no meaningful splice effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, which is below commonly used concern thresholds for splice disruption.

Recorded classification: Uncertain significance

León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final category thresholds with POLE-specific criterion specifications

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
1 / 1,613,298 alleles

gnomAD v4.1: 1 / 1,613,298 alleles. Recorded AF 6.19848e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
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
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 4 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The POLE c.4952+9A>G (p.?) variant has not been identified in the León-Castillo endometrial carcinoma recurrence table and has been reported in ClinVar as Likely benign by one clinical laboratory.

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07), which supports rarity but does not establish pathogenic enrichment.

SpliceAI predicts low splice impact for NM_006231.4 with a maximum delta score of 0.07, arguing against a clinically meaningful splicing effect.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals), which is below the project's PM2 threshold of 0.1% and supports rarity in the general population. Details ▾Hide ▴
Rule
Project generic rarity rule: PM2 when population frequency is below 0.1%.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AF 6.19848e-07
  • South Asian AF 1.09813e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingComputational splicing prediction supports no meaningful splice effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, which is below commonly used concern thresholds for splice disruption. Details ▾Hide ▴
Rule
Generic computational benign evidence applied from low predicted splice impact.
Evidence considered
  • SpliceAI max delta score 0.07
Sources
spliceai ↗

Not met · 4 · evaluated, threshold not reached

PS4 The local POLE framework limits PS4 to exact recurrent exonuclease-domain missense variants in the established pathogenic set with combined COSMIC and TCGA endometrial carcinoma counts of at least 10. This intronic variant is not listed in the recurrence table, and no germline case-control or multiple unrelated affected-proband evidence was identified. Details ▾Hide ▴
Rule
Local POLE PS4 applies only to exact recurrent pathogenic-set exonuclease-domain missense variants with combined EC count >=10.
Evidence considered
  • Not present in León-Castillo Supplementary Table S1 recurrent POLE variant list
  • ClinVar shows a single Likely benign clinical laboratory submission rather than affected-case enrichment
Sources
final_classification_frameworkvcep_path_250_323_s002clinvar ↗vcep_path_250_323
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, and no REVEL or BayesDel score is available for this intronic variant. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect; that support was not identified.
Evidence considered
  • SpliceAI maximum delta score 0.07 for NM_006231.4
  • REVEL not found
  • BayesDel not found
Sources
spliceai ↗
BA1 This variant does not meet the BA1 population threshold. Its gnomAD v4.1 allele frequency is 6.20e-07 overall and 1.10e-05 in the highest-frequency population, both well below the project's BA1 threshold of 1%. Details ▾Hide ▴
Rule
Project generic BA1 threshold: >1%.
Evidence considered
  • gnomAD v4.1 total AF 6.19848e-07
  • Highest subpopulation AF 1.09813e-05
Sources
gnomad_v4 ↗
BS1 This variant does not meet the BS1 population threshold. Its highest observed gnomAD v4.1 population frequency is 1.10e-05, which is below the project's BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
Project generic BS1 threshold: >0.3%.
Evidence considered
  • Highest subpopulation AF 1.09813e-05 in South Asian individuals
Sources
gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant. Details ▾Hide ▴
Still missing
  • Parental testing and de novo confirmation data were not available.
PS3 No published functional assay demonstrating an abnormal effect of this specific intronic variant was identified. Details ▾Hide ▴
Still missing
  • Variant-specific RNA or functional studies were not available.
PM3 No phase data or recessive case evidence relevant to PM3 were identified. Details ▾Hide ▴
Still missing
  • No trans-phase observations with a pathogenic variant were available.
PM4 This variant is intronic and does not directly demonstrate a protein length change. No RNA evidence was identified to show in-frame exon loss or other protein-length alteration. Details ▾Hide ▴
Still missing
  • Variant-specific RNA data would be needed to evaluate any protein-length effect.
PM6 No assumed de novo evidence without full parental confirmation was identified. Details ▾Hide ▴
Still missing
  • Parental-origin data were not available.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • Family segregation studies were not available.
PP4 No phenotype-specific evidence was identified to show that the clinical presentation is highly specific for a POLE-related disorder caused by this variant. Details ▾Hide ▴
Still missing
  • Detailed phenotype and testing-indication data were not available.
PP5 No reputable-source pathogenic classification was used as stand-alone evidence for this variant. Details ▾Hide ▴
Rule
PP5 was not used as an independent criterion.
BS2 No evidence was identified showing this variant in healthy adult individuals at a level sufficient for BS2. Details ▾Hide ▴
Still missing
  • Well-documented unaffected-carrier data were not available.
BS3 No published functional study demonstrating a normal effect of this specific variant was identified. Details ▾Hide ▴
Still missing
  • Variant-specific functional or RNA studies showing no abnormal effect were not available.
BS4 No segregation data were identified showing lack of segregation with disease. Details ▾Hide ▴
Still missing
  • Family segregation studies were not available.
BP2 No phase information was identified to assess BP2. Details ▾Hide ▴
Still missing
  • Cis/trans data with another pathogenic variant were not available.
BP3 This criterion was not assessed because the variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP5 No alternate molecular explanation sufficient to account for the phenotype independently of this variant was identified. Details ▾Hide ▴
Still missing
  • Comprehensive alternate-cause assessment was not available.
BP6 Although ClinVar contains a Likely benign submission for this variant, a reputable-source benign assertion was not used as stand-alone evidence. Details ▾Hide ▴
Rule
BP6 was not used as an independent criterion.
Evidence considered
  • ClinVar: Likely benign
  • single clinical laboratory
Sources
clinvar ↗
BP7 This intronic +9 variant has low predicted splice impact by SpliceAI, but no additional conservation-based or framework-specific BP7 assessment was available to support formal application of BP7. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.07
Still missing
  • Additional conservation or framework-specific noncoding BP7 guidance would strengthen assessment.
Sources
spliceai ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AAlthough POLE is flagged as eligible for generic PVS1 consideration at the gene level, this variant is an intronic +9 change and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice-site variants. PVS1 is therefore not applied. Details ▾Hide ▴
Rule
Generic PVS1 fallback applies only to eligible null-variant classes; this intronic +9 variant is outside those classes.
Evidence considered
  • POLE is gene-level PVS1 eligible in the generic framework
  • c.4952+9A>G is not a canonical splice-site or other default PVS1 null variant
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/APS1 applies to a different nucleotide change causing the same amino acid substitution. This intronic variant has no defined amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Rule
PS1 is limited to established amino acid substitutions.
Evidence considered
  • Protein consequence is p.?
PM1 N/AThe local POLE PM1 framework is restricted to exact exonuclease-domain hotspot or recurrent missense substitutions highlighted by León-Castillo et al. This intronic +9 variant is not a missense exonuclease-domain hotspot and is not listed in the recurrence table, so PM1 is not applicable. Details ▾Hide ▴
Rule
Local POLE PM1 is only for specified exonuclease-domain missense substitutions.
Evidence considered
  • Local PM1 scope is limited to exact hotspot or recurrent exonuclease-domain missense substitutions
  • Variant absent from Supplementary Table S1
Sources
final_classification_frameworkvcep_path_250_323vcep_path_250_323_s002
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This intronic variant has no amino acid substitution, so PM5 is not applicable. Details ▾Hide ▴
Rule
PM5 is limited to missense variants.
Evidence considered
  • Protein consequence is p.?
PP2 N/APP2 is a missense-based criterion and does not apply to this intronic variant. Details ▾Hide ▴
Rule
PP2 is limited to missense variants.
BP1 N/ABP1 is a missense-based criterion and does not apply to this intronic variant. Details ▾Hide ▴
Rule
BP1 is limited to missense variants.

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.4952+9A>G
Protein (HGVS p.)
NP_006222.2:p.?
GRCh38
chr12:132642497 T>C
GRCh37
chr12:133219083 T>C

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…
gnomAD v4.1 1 / 1,613,298 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,298 alleles · 0 hom
South Asian1 / 91,064 1.1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19848e-07; MAF= 0.00006%, 1/1613298 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09813e-05; MAF= 0.00110%, 1/91064 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingComputational splicing prediction supports no meaningful splice effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, which is below commonly used concern thresholds for splice disruption. Details ▾Hide ▴
Rule
Generic computational benign evidence applied from low predicted splice impact.
Evidence considered
  • SpliceAI max delta score 0.07
Sources
spliceai ↗
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, and no REVEL or BayesDel score is available for this intronic variant. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect; that support was not identified.
Evidence considered
  • SpliceAI maximum delta score 0.07 for NM_006231.4
  • REVEL not found
  • BayesDel not found
Sources
spliceai ↗
BP7 This intronic +9 variant has low predicted splice impact by SpliceAI, but no additional conservation-based or framework-specific BP7 assessment was available to support formal application of BP7. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.07
Still missing
  • Additional conservation or framework-specific noncoding BP7 guidance would strengthen assessment.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

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 1 / 1,613,298 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

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= 6.19848e-07; MAF= 0.00006%, 1/1613298 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09813e-05; MAF= 0.00110%, 1/91064 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).