POLEc.745C>AUncertain significance

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Variant interpretation report

POLE c.745C>A, p.(Arg249=)

NM_006231.4:c.745C>A NP_006222.2:p.(Arg249=) 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.

Key facts

Evidence used: 1 supporting (benign) · 1 moderate (pathogenic)
Expert rules: León-Castillo et al. 2020 custom POLE framework

Evidence considered

View criteria

Applied evidence criteria

PM2 (moderate): This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0 in both datasets, which is below the 0.1% PM2 threshold.
BP7 (supporting): This is a synonymous variant outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Available evidence does not support an effect on RNA splicing.

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

PM2Moderate

PM2 · moderate

This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0 in both datasets, which is below the 0.1% PM2 threshold.

Benign criteria applied · 1

BP7Supporting

BP7 · supporting

This is a synonymous variant outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Available evidence does not support an effect on RNA splicing.

Recorded classification: Uncertain significance

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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

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 · BP7 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

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 · 13 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The POLE c.745C>A (p.Arg249=) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by two clinical laboratory submissions.

This variant is absent from gnomAD v2.1 and gnomAD v4.1.

This variant is not listed among the recurrent or hotspot POLE exonuclease-domain substitutions in the León-Castillo POLE review materials.

This is a synonymous change outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0 in both datasets, which is below the 0.1% PM2 threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP7 SupportingThis is a synonymous variant outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Available evidence does not support an effect on RNA splicing. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).
Canonical splice consensus flag is false.
SpliceAI max delta score 0.03.

Sources

spliceai ↗pvs1_variant_assessment

Not met · 4 · evaluated, threshold not reached

PS4 This variant has not been reported in COSMIC and is not listed among the recurrent POLE endometrial carcinoma variants in Supplementary Table S1. The local POLE PS4 rule applies only to exact recurrent exonuclease-domain missense hotspot variants with combined COSMIC and TCGA endometrial carcinoma counts of at least 10, which is not met here. Details ▾Hide ▴

Evidence considered

COSMIC: no result found for POLE c.745C>A.
The variant was not found in Supplementary Table S1 recurrent POLE variants.

Sources

vcep_path_250_323_s002vcep_path_250_323final_classification_framework

PM1 This synonymous variant is not one of the exact POLE exonuclease-domain hotspot or recurrent missense substitutions specified in the local POLE PM1 framework, and no statistically significant hotspot evidence was identified at Arg249. Details ▾Hide ▴

Evidence considered

The variant is absent from the POLE hotspot/recurrent variant list in Supplementary Table S1.
Cancer Hotspots did not identify a hotspot row for R249.

Sources

vcep_path_250_323vcep_path_250_323_s002hotspots ↗final_classification_framework

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the >1% BA1 threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the >0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1.
Absent from gnomAD v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴

Still missing

Parental testing or a documented de novo report would be needed.

PS3 No published functional study was identified that directly tested this exact synonymous variant. Details ▾Hide ▴

Evidence considered

OncoKB did not provide variant-specific functional evidence for this change.

Still missing

Direct RNA or other variant-specific functional data would be needed.

Sources

oncokb ↗

PM3 No trans configuration data or recessive-case evidence were identified for this variant. Details ▾Hide ▴

Still missing

Phase information in affected individuals would be needed.

PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴

Still missing

A reported de novo occurrence without full confirmation would be needed.

PP1 No segregation data were identified for this variant. Details ▾Hide ▴

Still missing

Family segregation data would be needed.

PP4 No phenotype-specific evidence was identified to show that the observed clinical presentation is highly specific for a POLE-related disorder caused by this variant. Details ▾Hide ▴

Still missing

Detailed phenotype and gene-disease correlation data would be needed.

PP5 No independent use of external pathogenic assertions was made for this variant. Details ▾Hide ▴

Evidence considered

ClinVar reports a likely benign classification rather than a pathogenic assertion.

Sources

clinvar ↗

BS2 No dataset was identified showing this variant in well-phenotyped unaffected individuals at a frequency sufficient for BS2. Details ▾Hide ▴

Still missing

Observation in unaffected adults under an appropriate gene-specific framework would be needed.

BS3 No well-established functional study was identified showing a benign effect for this exact variant. Details ▾Hide ▴

Evidence considered

SpliceAI predicts no significant splice impact
but this is not a stand-alone validated functional assay.

Still missing

Variant-specific RNA or other functional evidence demonstrating no impact would be needed.

Sources

spliceai ↗

BS4 No evidence was identified that this variant fails to segregate with disease in a family. Details ▾Hide ▴

Still missing

Non-segregation data would be needed.

BP2 No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴

Still missing

Phase information would be needed.

BP5 No alternate molecular explanation or case-level context was identified that would support BP5 for this variant. Details ▾Hide ▴

Still missing

Detailed case-level molecular findings would be needed.

BP6 No independent use of external benign assertions was made for this criterion. Details ▾Hide ▴

Evidence considered

ClinVar reports this variant as likely benign
but no assertion-only criterion was applied here.

Sources

clinvar ↗

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a synonymous substitution and is not a nonsense, frameshift, or canonical ±1,2 splice variant, so the generic PVS1 loss-of-function framework does not apply. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).
The variant is not in a default PVS1 null-variant bucket.

Sources

pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗

PS1 N/AThis variant does not change the amino acid sequence, and no same-amino-acid pathogenic substitution basis for PS1 was identified. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).

Sources

clinvar ↗

PM4 N/AThis variant does not alter protein length or reading frame, so PM4 does not apply. Details ▾Hide ▴

Evidence considered

Protein consequence is synonymous with no predicted protein length change.

Sources

pvs1_variant_assessment

PM5 N/AThis criterion is for a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is synonymous, so PM5 does not apply. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).

Sources

clinvar ↗

PP2 N/APP2 is a missense criterion, and this variant is synonymous. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).

Sources

clinvar ↗

PP3 N/AThe local POLE PP3 rule is restricted to exact missense variants represented in the León-Castillo supplementary in silico tables. This synonymous variant is not listed in those tables, REVEL and BayesDel scores were not available, and SpliceAI does not support a damaging splicing effect (max delta score 0.03). Details ▾Hide ▴

Evidence considered

Variant not found in Supplementary Tables S2 or S3.
REVEL not found.
BayesDel not found.
SpliceAI max delta score 0.03.

Sources

vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗final_classification_framework

BP1 N/ABP1 is a missense criterion, and this variant is synonymous. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).

Sources

clinvar ↗

BP3 N/ABP3 applies to certain in-frame variants in repetitive regions and does not apply to this synonymous substitution. Details ▾Hide ▴

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).

Sources

clinvar ↗

BP4 N/AThe local POLE BP4 rule is restricted to exact missense variants represented in the León-Castillo supplementary in silico tables. This synonymous variant is not listed in those tables, and benign splicing prediction is better captured under BP7. Details ▾Hide ▴

Evidence considered

Variant not found in Supplementary Tables S2 or S3.
SpliceAI max delta score 0.03.

Sources

vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗final_classification_framework

Identifiers

Gene: POLE
Transcript: NM_006231.4
Coding (HGVS c.): NM_006231.4:c.745C>A
Protein (HGVS p.): NP_006222.2:p.(Arg249=)
GRCh38: chr12:132677419 G>T
GRCh37: chr12:133254005 G>T

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 — 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

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

Protein consequence is p.(Arg249=)/p.(R249=).
Canonical splice consensus flag is false.
SpliceAI max delta score 0.03.

Sources

spliceai ↗pvs1_variant_assessment

Evidence considered

Variant not found in Supplementary Tables S2 or S3.
REVEL not found.
BayesDel not found.
SpliceAI max delta score 0.03.

Sources

vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗final_classification_framework

Evidence considered

Variant not found in Supplementary Tables S2 or S3.
SpliceAI max delta score 0.03.

Sources

vcep_path_250_323_s003vcep_path_250_323_s004spliceai ↗final_classification_framework

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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 Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.