0%
POLEc.1708C>AUncertain significance
Print report
Variant interpretation report

POLE c.1708C>A, p.(Leu570Met)

NM_006231.4:c.1708C>A NP_006222.2:p.(Leu570Met) 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
PM2Moderate
PM2 · moderate

NM_006231.4:c.1708C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the PM2 criterion (allele frequency <0.1% in large population databases).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.267 (below the 0.5 pathogenic threshold, in benign-leaning range), BayesDel score is -0.221 (negative, predicting benign impact), and SpliceAI predicts no splicing alteration (max delta score 0.06). The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE BP4 rule does not apply; this assessment uses the generic ACMG/AMP BP4 criterion based on the converging in silico evidence.

Recorded classification: Uncertain significance

The León-Castillo et al. 2020 custom POLE framework (gene_framework) was applied. Only one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. No pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied. Per the framework (which mirrors generic ACMG/AMP 2015 combination logic), all other combinations default to Uncertain Significance.

02The sources

Evidence at a glance

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

SpliceAI score
0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions

4 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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
No matching record reported

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

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.

26 criteria with recorded statuses: 2 met · 10 not met · 11 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain.

The variant is absent from gnomAD v2.1 (exomes) and v4.1 (exomes) population databases, meeting PM2 at moderate strength (PM2_Moderate).

Multiple in silico tools predict a benign impact: REVEL score 0.267 (benign-leaning, below the 0.5 pathogenic threshold), BayesDel score -0.221 (benign), and SpliceAI max delta 0.06 (no splice impact). This meets BP4 at supporting benign strength (BP4_Supporting).

The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories (Variation ID 405767). It is not among the established POLE exonuclease-domain hotspot mutations identified by León-Castillo et al. 2020, and is absent from COSMIC and Cancer Hotspots.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. The variant is classified as Variant of Uncertain Significance (VUS) under the León-Castillo et al. 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.

Met · 2

PM2 ModerateNM_006231.4:c.1708C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the PM2 criterion (allele frequency <0.1% in large population databases). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.267 (below the 0.5 pathogenic threshold, in benign-leaning range), BayesDel score is -0.221 (negative, predicting benign impact), and SpliceAI predicts no splicing alteration (max delta score 0.06). The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE BP4 rule does not apply; this assessment uses the generic ACMG/AMP BP4 criterion based on the converging in silico evidence. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.267 (benign-leaning).
  • BayesDel: -0.221 (benign).
  • SpliceAI: max delta 0.06 (no impact).
Sources
revelbayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

PS1 No established pathogenic variant with a different nucleotide change producing the same amino acid substitution (p.Leu570Met) has been identified at this codon. Details ▾Hide ▴
Evidence considered
  • No pathogenic comparator at codon 570.
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_006231.4:c.1708C>A (p.Leu570Met). The variant is absent from COSMIC and OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional data. COSMIC: not reported.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 NM_006231.4:c.1708C>A (p.Leu570Met) is absent from both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1 of León-Castillo et al. 2020. The custom POLE framework PS4_Supporting threshold (combined EC count >=10, belonging to established pathogenic set) is not met. Variant is not recurrent in available somatic datasets. Details ▾Hide ▴
Evidence considered
  • Absent from COSMIC and TCGA EC cohorts
  • 0 cases in Supplementary Table S1.
Still missing
  • No germline case-control data available.
Sources
vcep_path_250_323_s002
PM1 p.Leu570Met (residue 570) is not one of the five established POLE exonuclease-domain hotspot variants (P286R, V411L, S297F, A456P, S459F) per the León-Castillo et al. 2020 custom framework. It is not among the PM1_Moderate variants (F367S, L424I, M295R, P436R, M444K, D368Y) or PM1_Supporting variants (A465V, L424V, T278M, A428T). Residue 570 lies outside the exonuclease domain (~268-471) in the polymerase domain. No mutational hotspot or critical functional domain has been established at this position. Details ▾Hide ▴
Evidence considered
  • Variant not among any listed hotspot or recurrent pathogenic residues. Residue 570 lies outside the exonuclease domain.
Sources
vcep_path_250_323vcep_path_250_323_s002
PM5 No pathogenic missense variant at the same codon (Leu570) with a different amino acid change was identified through ClinVar candidate harvesting or the León-Castillo supplementary tables. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants identified.
Sources
pm5_candidates
PP3 The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE PP3 rule does not apply. Under generic ACMG/AMP, REVEL score is 0.267 (below the 0.5 pathogenic threshold) and BayesDel score is -0.221 (negative, benign-leaning). SpliceAI max delta score is 0.06, predicting no splice impact. Multiple computational tools do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.267 (benign-leaning).
  • BayesDel: -0.221 (benign).
  • SpliceAI: max delta 0.06 (no splice impact).
  • Absent from Supplementary Tables S2 and S3.
Sources
revelbayesdelspliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004
PP5 No reputable source has classified NM_006231.4:c.1708C>A as pathogenic. ClinVar reports this variant as Uncertain significance (Variation ID 405767, 4 clinical laboratories, criteria provided single submitter). OncoKB reports Unknown Oncogenic Effect. None of the reviewed literature sources classify this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • 4 submitters.
  • OncoKB: Unknown Oncogenic Effect.
Sources
clinvar ↗oncokb ↗253941752574186828492532
BA1 NM_006231.4:c.1708C>A is absent from gnomAD v2.1 and v4.1. The BA1 threshold of >1% allele frequency in population databases is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_006231.4:c.1708C>A is absent from gnomAD v2.1 and v4.1. The BS1 threshold of >0.3% allele frequency in population databases is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP6 No reputable source has classified NM_006231.4:c.1708C>A as benign. ClinVar reports this variant as Uncertain significance (Variation ID 405767). BP6 requires a reputable source to report the variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • not benign.
Sources
clinvar ↗253941752574186828492532

Not assessed · 11 · no assessment recorded

PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PM6 No de novo data available for this variant. PM6 cannot be assessed without a confirmed de novo observation. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No co-segregation data available for this variant in affected families. Details ▾Hide ▴
Still missing
  • No segregation analysis data available.
PP2 No HCI prior probability score or gene-level missense constraint metrics (z-score, pLI) are available for POLE to evaluate the rate of benign missense variation. PP2 cannot be reliably applied without these data. Details ▾Hide ▴
Evidence considered
  • HCI prior: not found. No gene-level missense constraint data available.
Still missing
  • Missing gene-level missense constraint z-score or pLI for POLE.
PP4 No patient-specific phenotype or family history data are available for this case. PP4 cannot be evaluated without clinical context. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided.
BS2 No data available regarding observation of this variant in healthy adult individuals. The variant is absent from gnomAD, so no homozygous or hemizygous counts are available for BS2 evaluation. Details ▾Hide ▴
Still missing
  • No observation data in healthy individuals.
BS3 No well-established in vitro or in vivo functional studies have been identified showing no damaging effect for NM_006231.4:c.1708C>A. Absent from COSMIC, and OncoKB shows no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • No functional studies available.
Still missing
  • No functional studies evaluating this variant.
Sources
oncokb ↗
BS4 No segregation data are available to evaluate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 No data available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No trans-configuration data.
BP5 No data available regarding identification of an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses.
PS5 No data available regarding detection of this variant in trans with a pathogenic variant for a recessive disorder. Details ▾Hide ▴
Still missing
  • No trans-configuration data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.1708C>A is a missense variant (p.Leu570Met). PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2). This variant does not fall into any PVS1 bucket under PMC6185798. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant.
Sources
pvs1_generic_framework ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. In POLE, both missense variants (particularly in the exonuclease domain) and truncating variants are established mechanisms of disease, and the gene is known to harbor pathogenic missense variants. BP1 is therefore not applicable. Details ▾Hide ▴
Evidence considered
  • POLE pathogenic variants include both missense and truncating types.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_006231.4:c.1708C>A is a missense variant (p.Leu570Met), not synonymous. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.1708C>A
Protein (HGVS p.)
NP_006222.2:p.(Leu570Met)
GRCh38
chr12:132672301 G>T
GRCh37
chr12:133248887 G>T
ClinVar
405767

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
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -9 bp
0.060
SpliceAI acceptor gainat +21 bp
0.000
SpliceAI donor lossat -320 bp
0.000
SpliceAI donor gainat +279 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.010

Other predictors

REVEL
0.267
BayesDel
-0.221

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.267 (below the 0.5 pathogenic threshold, in benign-leaning range), BayesDel score is -0.221 (negative, predicting benign impact), and SpliceAI predicts no splicing alteration (max delta score 0.06). The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE BP4 rule does not apply; this assessment uses the generic ACMG/AMP BP4 criterion based on the converging in silico evidence. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.267 (benign-leaning).
  • BayesDel: -0.221 (benign).
  • SpliceAI: max delta 0.06 (no impact).
Sources
revelbayesdelspliceai ↗
PP3 The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE PP3 rule does not apply. Under generic ACMG/AMP, REVEL score is 0.267 (below the 0.5 pathogenic threshold) and BayesDel score is -0.221 (negative, benign-leaning). SpliceAI max delta score is 0.06, predicting no splice impact. Multiple computational tools do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.267 (benign-leaning).
  • BayesDel: -0.221 (benign).
  • SpliceAI: max delta 0.06 (no splice impact).
  • Absent from Supplementary Tables S2 and S3.
Sources
revelbayesdelspliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_006231.4:c.1708C>A is a missense variant (p.Leu570Met), not synonymous. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.267. BayesDel score = -0.220802.

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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 Recorded maximum delta 0.060 Open source ↗
ClinVar 4 Uncertain significance 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 Uncertain significance (4 clinical laboratories). (ClinVarID = 405767)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.267. BayesDel score = -0.220802.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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 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.