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POLEc.889T>CUncertain significance
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Variant interpretation report

POLE c.889T>C, p.(Ser297Pro)

NM_006231.4:c.889T>C NP_006222.2:p.(Ser297Pro) 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 Not recorded. 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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

The variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity. No explicit POLE-specific PM2 frequency cutoff was retrieved, so this is a generic ACMG rarity assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Generic ACMG/AMP classification using the retrieved generic_acmg_combination_rules fallback (Richards et al. 2015) because no gene-specific VCEP framework was retrieved.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

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

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 4 not met · 20 not assessed · 3 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

POLE p.(Ser297Pro) is absent from gnomAD v2.1.

The variant is also absent from gnomAD v4.1, supporting rarity, although no explicit POLE-specific population cutoff was retrieved.

SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, but no explicit computational threshold framework was retrieved to convert the available in silico data into PP3 or BP4.

No ClinVar classification has been reported for this variant.

With PM2 applied and no additional pathogenic or benign criteria established, this variant is classified as a variant of uncertain significance under the retrieved generic ACMG/AMP combination rules.

Met · 1

PM2 ModerateThe variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity. No explicit POLE-specific PM2 frequency cutoff was retrieved, so this is a generic ACMG rarity assessment. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Still missing
  • No gene-specific population threshold was retrieved.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PM1 This residue was not identified as a statistically significant hotspot, and no critical functional domain evidence meeting PM1 was retrieved. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots search found no hotspot row for POLE S297.
BA1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet a stand-alone benign population frequency criterion. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet a benign strong population frequency criterion. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Benign computational evidence was not established. SpliceAI shows a maximum delta score of 0.00, but REVEL is 0.774 and no retrieved framework supported an overall benign in silico interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.774.
Sources
spliceai ↗

Not assessed · 20 · no assessment recorded

PS1 No retrieved source established that this amino-acid change matches a previously classified pathogenic variant at the same residue with the same protein consequence. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for this variant.
Still missing
  • No same-amino-acid pathogenic comparison was retrieved.
Sources
clinvar ↗
PS2 No de novo data were retrieved. Details ▾Hide ▴
Still missing
  • Parental testing and confirmed de novo status were not available.
PS3 No well-established functional assay data were retrieved for this variant. Details ▾Hide ▴
Still missing
  • Variant-specific functional studies were not available in the workspace.
PS4 No case-control enrichment or multiple independent affected observations were retrieved. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result; no PMIDs were retrieved.
Still missing
  • Affected-case counts and control comparison data were not available.
Sources
clinvar ↗
PM3 No phase data or occurrence with another pathogenic allele were retrieved. Details ▾Hide ▴
Still missing
  • Phase and allelic context data were not available.
PM5 No different pathogenic missense change at codon 297 was retrieved. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for this variant.
Still missing
  • Codon-specific pathogenic comparison data were not available.
Sources
clinvar ↗
PM6 No assumed de novo data without parental confirmation were retrieved. Details ▾Hide ▴
Still missing
  • Family-based de novo information was not available.
PP1 No segregation data were retrieved. Details ▾Hide ▴
Still missing
  • Pedigree segregation information was not available.
PP2 No retrieved gene-level evidence established that missense variation is a predominant disease mechanism suitable for PP2 application. Details ▾Hide ▴
Still missing
  • Gene-level missense mechanism evidence was not retrieved.
PP3 REVEL is 0.774 and SpliceAI maximum delta score is 0.00, but no explicit computational threshold framework applicable to this case was retrieved to convert these values into PP3. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.774.
  • SpliceAI max delta score 0.00.
Still missing
  • No explicit PP3 threshold rule was retrieved.
Sources
spliceai ↗
PP4 No phenotype-specific evidence for a highly specific POLE-associated presentation was provided. Details ▾Hide ▴
Still missing
  • Clinical phenotype and testing context were not available.
PP5 No reputable external pathogenic classification was retrieved. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
Still missing
  • No classified external submission was available.
Sources
clinvar ↗
BS2 No observations in healthy adult individuals inconsistent with disease penetrance were retrieved. Details ▾Hide ▴
Still missing
  • Unaffected carrier data were not available.
BS3 No well-established functional evidence demonstrating no damaging effect was retrieved. Details ▾Hide ▴
Still missing
  • Benign functional assay data were not available.
BS4 No lack-of-segregation data were retrieved. Details ▾Hide ▴
Still missing
  • Family segregation data were not available.
BP1 No retrieved gene-level evidence supported BP1 for this missense variant. Details ▾Hide ▴
Still missing
  • Gene-specific mechanism evidence was not retrieved.
BP2 No phase data with another pathogenic variant were retrieved. Details ▾Hide ▴
Still missing
  • Cis/trans information was not available.
BP3 No evidence was retrieved that the variant lies in a repetitive region without known function. Details ▾Hide ▴
Still missing
  • Protein-region context relevant to BP3 was not available.
BP5 No alternate molecular explanation accounting for the phenotype was retrieved. Details ▾Hide ▴
Still missing
  • Phenotype and alternate-cause data were not available.
BP6 No reputable benign classification was retrieved. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result.
Still missing
  • No classified external benign submission was available.
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.889T>C is a missense substitution predicted as p.(Ser297Pro) / p.(S297P), not a null variant in a gene where loss of function is being evaluated under PVS1. Details ▾Hide ▴
Evidence considered
  • Normalization identifies a missense protein change: NP_006222.2:p.(Ser297Pro) / p.(S297P).
PM4 N/AThis is a single amino-acid substitution and does not produce a protein length change. Details ▾Hide ▴
Evidence considered
  • Predicted consequence is missense p.(Ser297Pro).
BP7 N/ABP7 is for synonymous or certain intronic variants without predicted splice impact; this variant is missense. Details ▾Hide ▴
Evidence considered
  • Predicted consequence is missense p.(Ser297Pro).
  • SpliceAI max delta score 0.00.
Sources
spliceai ↗

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.889T>C
Protein (HGVS p.)
NP_006222.2:p.(Ser297Pro)
GRCh38
chr12:132676566 A>G
GRCh37
chr12:133253152 A>G

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 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

BP4 Benign computational evidence was not established. SpliceAI shows a maximum delta score of 0.00, but REVEL is 0.774 and no retrieved framework supported an overall benign in silico interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.774.
Sources
spliceai ↗
PP3 REVEL is 0.774 and SpliceAI maximum delta score is 0.00, but no explicit computational threshold framework applicable to this case was retrieved to convert these values into PP3. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.774.
  • SpliceAI max delta score 0.00.
Still missing
  • No explicit PP3 threshold rule was retrieved.
Sources
spliceai ↗
BP7 N/ABP7 is for synonymous or certain intronic variants without predicted splice impact; this variant is missense. Details ▾Hide ▴
Evidence considered
  • Predicted consequence is missense p.(Ser297Pro).
  • SpliceAI max delta score 0.00.
Sources
spliceai ↗

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 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
Cancer hotspots Captured Cancer Hotspots source record
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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m

Somatic

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