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POLEc.1718G>AUncertain significance
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Variant interpretation report

POLE c.1718G>A, p.(Arg573Gln)

NM_006231.4:c.1718G>A NP_006222.2:p.(Arg573Gln) 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: 0
Pathogenic criteria applied · 1
PM2Met
PM2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles) in Middle Eastern individuals. These values are below the project's default PM2 rarity threshold of 0.1%, supporting PM2.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

León-Castillo et al. 2020 custom POLE framework for criterion specification, using ACMG/AMP 2015 final classification combination thresholds as defined in the explicit final-classification framework.

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
3 / 1,614,158 alleles

gnomAD v4.1: 3 / 1,614,158 alleles. Recorded AF 1.85855e-06. 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.

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.

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: 1 met · 6 not met · 15 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.1718G>A (p.Arg573Gln) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar as uncertain significance by 3 clinical laboratories.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles), which remains below the 0.1% PM2 rarity threshold.

p.Arg573Gln is not listed among the recurrent POLE exonuclease-domain variants in León-Castillo et al. Supplementary Table S1 and was not identified in the Cancer Hotspots review, which does not support PM1 or the POLE-specific PS4 recurrence rule.

Available computational evidence does not support a protein-damaging or benign in silico assignment because this exact variant is not listed in the POLE supplementary in silico tables, REVEL is 0.228, and SpliceAI shows a possible splice impact with a max delta score of 0.20.

Met · 1

PM2 MetThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles) in Middle Eastern individuals. These values are below the project's default PM2 rarity threshold of 0.1%, supporting PM2. Details ▾Hide ▴
Rule
Generic population-frequency fallback: PM2 when allele frequency is below 0.1%.
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1 total AF=1.85855e-06
  • gnomAD v4.1 highest population AF=0.000165017
Sources
output/evidence.jsonoutput/case_summary.json

Not met · 6 · evaluated, threshold not reached

PS4 The local POLE framework applies PS4 only to exact recurrent exonuclease-domain variants that are present in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic set. p.Arg573Gln was not found in COSMIC and was not listed in Supplementary Table S1, so this criterion is not met. Details ▾Hide ▴
Rule
Local POLE custom PS4_Supporting rule from León-Castillo et al. 2020.
Evidence considered
  • COSMIC: no result found
  • Supplementary Table S1: variant not listed
  • custom POLE PS4 rule requires recurrent pathogenic EC variant with combined count >=10
Sources
output/final_classification_framework.jsonoutput/evidence.jsonvcep_db/POLE/files/PATH-250-323-s002.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335
PM1 The local POLE framework restricts PM1 to specific exact exonuclease-domain hotspot or recurrent pathogenic substitutions from León-Castillo et al. 2020. p.Arg573Gln is not one of the exact PM1-listed substitutions and was not identified in Supplementary Table S1 or Cancer Hotspots, so PM1 is not met. Details ▾Hide ▴
Rule
Local POLE custom PM1 rule from León-Castillo et al. 2020.
Evidence considered
  • custom PM1 rule lists exact substitutions only
  • Supplementary Table S1: variant not listed
  • Cancer Hotspots: no hotspot row found for R573
Sources
output/final_classification_framework.jsonoutput/evidence.jsonvcep_db/POLE/files/PATH-250-323-s002.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335
PP3 The local POLE framework applies PP3 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result. p.Arg573Gln was not listed in those supplementary tables. In the generic computational review, REVEL is 0.228 and SpliceAI shows only a borderline signal at 0.20, so available in silico evidence does not support a deleterious PP3 assignment. Details ▾Hide ▴
Rule
Local POLE custom PP3 rule; generic in silico fallback does not support deleterious computational evidence here.
Evidence considered
  • Supplementary Tables S2 and S3: variant not listed
  • REVEL=0.228
  • SpliceAI max delta=0.20
Sources
output/final_classification_framework.jsonoutput/evidence.jsonoutput/case_summary.jsonvcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335
BA1 The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BA1 threshold of 1%. This variant therefore does not meet BA1. Details ▾Hide ▴
Rule
Generic population-frequency fallback: BA1 when allele frequency exceeds 1%.
Evidence considered
  • gnomAD v4.1 highest population AF=0.000165017
  • BA1 threshold=1%
Sources
output/evidence.jsonoutput/case_summary.json
BS1 The highest observed population frequency is 0.000165017 (0.01650%, 1/6060 alleles), which is below the project's BS1 threshold of 0.3%. This variant therefore does not meet BS1. Details ▾Hide ▴
Rule
Generic population-frequency fallback: BS1 when allele frequency exceeds 0.3%.
Evidence considered
  • gnomAD v4.1 highest population AF=0.000165017
  • BS1 threshold=0.3%
Sources
output/evidence.jsonoutput/case_summary.json
BP4 The local POLE framework applies BP4 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely benign and at least four benign in silico results. p.Arg573Gln was not listed in those tables. In the generic computational review, REVEL is low at 0.228, but SpliceAI shows a possible splice impact with a max delta score of 0.20 rather than clearly no splice effect, so BP4 is not met. Details ▾Hide ▴
Rule
Local POLE custom BP4 rule; generic in silico fallback does not provide clear benign computational support because predicted splice impact is borderline.
Evidence considered
  • Supplementary Tables S2 and S3: variant not listed
  • REVEL=0.228
  • SpliceAI max delta=0.20
Sources
output/final_classification_framework.jsonoutput/evidence.jsonoutput/case_summary.jsonvcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335

Not assessed · 15 · no assessment recorded

PS1 No evidence was identified showing that a different nucleotide change causes the same p.Arg573Gln amino acid substitution and has already been established as pathogenic or likely pathogenic, so PS1 cannot be assessed from the available data. Details ▾Hide ▴
Evidence considered
  • ClinVar lists this variant as uncertain significance
  • no PS1-specific comparison evidence retrieved
Still missing
  • No same-amino-acid pathogenic comparison variant was retrieved.
Sources
output/case_summary.jsonoutput/evidence.json
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified, so PS2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • no de novo evidence retrieved
Still missing
  • No de novo case-level data were identified.
Sources
output/literature_pass.json
PS3 No well-established functional studies demonstrating a damaging effect of p.Arg573Gln were identified, so PS3 cannot be applied. Details ▾Hide ▴
Evidence considered
  • no functional study evidence retrieved
Still missing
  • No variant-specific functional assay data were retrieved.
Sources
output/literature_pass.jsonoutput/evidence.json
PM3 No evidence was identified showing this variant in trans with another pathogenic variant in a recessive disorder context, so PM3 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no PM3-relevant case data retrieved
Still missing
  • No phase or biallelic case data were identified.
Sources
output/literature_pass.json
PM5 No pathogenic or likely pathogenic missense comparison variant at the same amino acid residue was identified in the available evidence, so PM5 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar evidence for this variant only
  • no PM5-specific same-residue evidence retrieved
Still missing
  • No codon 573 pathogenic comparison variant was retrieved.
Sources
output/case_summary.jsonoutput/evidence.json
PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 cannot be applied. Details ▾Hide ▴
Evidence considered
  • no PM6-relevant evidence retrieved
Still missing
  • No de novo evidence was identified.
Sources
output/literature_pass.json
PP1 No segregation data were identified to show that this variant tracks with disease in affected family members, so PP1 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no segregation evidence retrieved
Still missing
  • No family segregation data were identified.
Sources
output/literature_pass.json
PP2 No gene-specific evidence was retrieved to show that pathogenic POLE variation is predominantly missense with a low rate of benign missense variation, so PP2 cannot be assessed from the available data. Details ▾Hide ▴
Evidence considered
  • local POLE framework does not provide a PP2 rule
Still missing
  • No PP2 gene-level missense calibration was retrieved.
Sources
output/final_classification_framework.json
PP4 No phenotype or family history data specific enough to establish a highly specific POLE-related clinical presentation were identified, so PP4 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no phenotype-specific evidence retrieved
Still missing
  • No case phenotype details were provided.
Sources
output/case_summary.json
BS2 No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2, so the criterion cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no BS2-specific healthy carrier data retrieved
Still missing
  • No unaffected carrier evidence was identified.
Sources
output/evidence.json
BS3 No well-established functional studies demonstrating no damaging effect of p.Arg573Gln were identified, so BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
  • no BS3-relevant functional evidence retrieved
Still missing
  • No benign functional assay data were retrieved.
Sources
output/literature_pass.json
BS4 No segregation evidence showing lack of cosegregation with disease was identified, so BS4 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no BS4-relevant family data retrieved
Still missing
  • No non-segregation data were identified.
Sources
output/literature_pass.json
BP1 No gene-specific evidence was retrieved showing that POLE disease is primarily caused by truncating variants with missense variants rarely pathogenic, so BP1 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • POLE framework does not provide a BP1 rule
Still missing
  • No BP1 gene-level calibration was retrieved.
Sources
output/pvs1_gene_context.jsonoutput/final_classification_framework.json
BP2 No phase data or co-occurrence evidence with another pathogenic variant were identified, so BP2 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no BP2-relevant data retrieved
Still missing
  • No co-occurrence or phase evidence was identified.
Sources
output/literature_pass.json
BP5 No evidence was identified showing an alternate molecular cause that fully explains the phenotype, so BP5 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • no BP5-relevant phenotype or molecular context retrieved
Still missing
  • No alternate molecular diagnosis data were identified.
Sources
output/case_summary.json
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework applies to nonsense, frameshift, or canonical ±1,2 splice variants rather than to p.(Arg573Gln). Available evidence does not support a loss-of-function PVS1 mechanism for this specific change. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 recommendations are not triggered for this missense variant.
Evidence considered
  • pvs1_variant_assessment: apply_generic_pvs1_framework=false
  • variant bucket=other
  • canonical_splice_consensus=false
Sources
output/pvs1_variant_assessment.jsonoutput/pvs1_gene_context.jsonClinGen SVI PVS1 recommendations (PMC6185798)
PM4 N/APM4 applies to protein length changes such as in-frame insertions, in-frame deletions, or stop-loss variants. This is a missense substitution and does not alter protein length. Details ▾Hide ▴
Evidence considered
  • protein change: p.(Arg573Gln)
Sources
output/case_summary.json
PP5 N/AClinVar reports this variant as uncertain significance, and assertion-only criteria are not applied as independent evidence in this review. PP5 is therefore not applicable. Details ▾Hide ▴
Rule
Assertion-only criteria are not used as standalone evidence.
Evidence considered
  • ClinVar: uncertain significance, 3 clinical laboratories
Sources
output/evidence.jsonoutput/case_summary.json
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions without known function. This is a missense substitution, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • protein change: p.(Arg573Gln)
Sources
output/case_summary.json
BP6 N/AClinVar does not provide a benign or likely benign expert assertion for this variant, and assertion-only criteria are not applied as independent evidence. BP6 is therefore not applicable. Details ▾Hide ▴
Rule
Assertion-only criteria are not used as standalone evidence.
Evidence considered
  • ClinVar: uncertain significance, not benign or likely benign
Sources
output/evidence.jsonoutput/case_summary.json
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • protein change: p.(Arg573Gln)
  • variant class is missense
Sources
output/case_summary.jsonoutput/evidence.json

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.1718G>A
Protein (HGVS p.)
NP_006222.2:p.(Arg573Gln)
GRCh38
chr12:132672291 C>T
GRCh37
chr12:133248877 C>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…
gnomAD v4.1 3 / 1,614,158 alleles AF 1.86e-06 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,158 alleles · 0 hom
Middle Eastern1 / 6,060 0.00017
Admixed American1 / 60,010 1.7e-05
Remaining individuals1 / 62,512 1.6e-05
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85855e-06; MAF= 0.00019%, 3/1614158 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 The local POLE framework applies PP3 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely disease causing and no more than one benign in silico result. p.Arg573Gln was not listed in those supplementary tables. In the generic computational review, REVEL is 0.228 and SpliceAI shows only a borderline signal at 0.20, so available in silico evidence does not support a deleterious PP3 assignment. Details ▾Hide ▴
Rule
Local POLE custom PP3 rule; generic in silico fallback does not support deleterious computational evidence here.
Evidence considered
  • Supplementary Tables S2 and S3: variant not listed
  • REVEL=0.228
  • SpliceAI max delta=0.20
Sources
output/final_classification_framework.jsonoutput/evidence.jsonoutput/case_summary.jsonvcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335
BP4 The local POLE framework applies BP4 only when the exact variant is present in Supplementary Table S2 or S3 with a REVEL class of likely benign and at least four benign in silico results. p.Arg573Gln was not listed in those tables. In the generic computational review, REVEL is low at 0.228, but SpliceAI shows a possible splice impact with a max delta score of 0.20 rather than clearly no splice effect, so BP4 is not met. Details ▾Hide ▴
Rule
Local POLE custom BP4 rule; generic in silico fallback does not provide clear benign computational support because predicted splice impact is borderline.
Evidence considered
  • Supplementary Tables S2 and S3: variant not listed
  • REVEL=0.228
  • SpliceAI max delta=0.20
Sources
output/final_classification_framework.jsonoutput/evidence.jsonoutput/case_summary.jsonvcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxLeón-Castillo et al. 2020 J Pathol 250:323-335
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • protein change: p.(Arg573Gln)
  • variant class is missense
Sources
output/case_summary.jsonoutput/evidence.json

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).

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 3 / 1,614,158 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 ↗
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

This variant is present in gnomAD v4.1 (AF= 1.85855e-06; MAF= 0.00019%, 3/1614158 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).

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 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.