About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.4411C>T, p.(Arg1471Cys)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.00835% (21/251,470 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00254% (41/1,614,222 alleles, 0 homozygotes). Highest subpopulation frequency is East Asian at 0.043% (v2.1). Allele frequency is well below the 0.1% threshold for PM2, but the variant is not absent from population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Only one supporting-level criterion (PM2_Supporting) was met. The León-Castillo et al. 2020 custom POLE framework does not alter the generic ACMG/AMP 2015 final-category thresholds. Under both the local framework and generic rules, a single supporting criterion is insufficient to reach Likely Pathogenic (minimum: PVS1+1Moderate, 1Strong+1Moderate, 3Moderate, 2Moderate+2Supporting, or 1Moderate+4Supporting) or Likely Benign (minimum: 1StrongBenign+1SupportingBenign or 2SupportingBenign). The evidence falls squarely into the uncertain significance category.
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
41 / 1,614,222 alleles
gnomAD v4.1: 41 / 1,614,222 alleles. Recorded AF 2.53992e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.3509e-05; MAF= 0.00835%, 21/251470 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434924; MAF= 0.04349%, 8/18394 alleles, homozygotes = 0); grpmax FAF= 0.00021571.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions
7 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57693254, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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: 1 met · 23 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006231.4:c.4411C>T (p.Arg1471Cys) is a missense variant in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268-471).
This variant is present at very low frequency in gnomAD: v2.1 AF=0.00835% (21/251,470 alleles) and v4.1 AF=0.00254% (41/1,614,222 alleles), with zero homozygotes in either dataset (PM2_Supporting).
The variant is absent from all León-Castillo et al. 2020 supplementary tables (S1, S2, S3) and is not one of the five established pathogenic exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F).
Computational predictions are mixed: REVEL 0.334 (borderline, below pathogenic threshold of 0.5), BayesDel 0.016 (benign range), SpliceAI max delta 0.01 (no predicted splicing impact). These do not support a deleterious effect per PP3 or a benign effect per BP4.
Five publications were cited by ClinVar submitters or identified in literature review. Full-text review confirmed none mention NM_006231.4:c.4411C>T or p.Arg1471Cys.
ClinVar reports this variant as Uncertain significance (VariationID 240513, 7 clinical laboratories, criteria provided single submitter). No expert panel review has been conducted.
This variant has been reported in COSMIC (COSV57693254, n=5 somatic occurrences), but somatic recurrence does not provide germline pathogenicity evidence.
Total evidence: PM2_Supporting (1 supporting pathogenic criterion). No benign criteria met. Classification remains Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingThis variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.00835% (21/251,470 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.00254% (41/1,614,222 alleles, 0 homozygotes). Highest subpopulation frequency is East Asian at 0.043% (v2.1). Allele frequency is well below the 0.1% threshold for PM2, but the variant is not absent from population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 21/251
- 470 alleles (AF=0.00835%)
- v4.1: 41/1
- 614
- 222 alleles (AF=0.00254%)
- 0 homozygotes
- grpmax FAF=0.00022.
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No known pathogenic variant with the same amino acid change (p.Arg1471Cys) has been identified in ClinVar or the literature. Variant is classified as VUS by all 7 ClinVar submitters. Details ▾Hide ▴
Evidence considered
- No pathogenic or likely pathogenic classification for p.Arg1471Cys at this codon.
Sources
PS2 No documented de novo occurrence for NM_006231.4:c.4411C>T was identified in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
- No de novo data available for this variant.
PS3 No variant-specific functional data or systematic range characterization including position 1471 was identified. The variant lies outside the exonuclease domain (residues ~268-471) in the C-terminal polymerase region. No full-text publication mentioned this variant or functionally characterized the region spanning codon 1471. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant
- REVEL 0.334 (borderline)
- BayesDel 0.016 (benign range) do not constitute functional evidence.
Still missing
- No experimental functional characterization of p.Arg1471Cys or systematic range including position 1471.
PS4 The León-Castillo et al. 2020 custom PS4 rule only applies to the five established hotspot variants (P286R, V411L, A456P, S297F) with combined EC count ≥10 in Supplementary Table S1. p.Arg1471Cys is absent from Table S1 and does not meet the custom framework criteria. No germline case-control data is available for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from León-Castillo Supplementary Table S1
- not one of five established pathogenic hotspots.
Still missing
- No case-control evidence for this variant.
Sources
vcep_path_250_323_s002clinvar ↗
PM1 The León-Castillo et al. 2020 custom PM1 rules apply to specific exonuclease-domain hotspot and recurrent missense variants (P286R, V411L, S297F, A456P, S459F at Strong; F367S, L424I, M295R, P436R, M444K, D368Y at Moderate; A465V, L424V, T278M, A428T at Supporting). p.Arg1471Cys is not among these variants. Additionally, position 1471 is in the C-terminal polymerase domain, far outside the exonuclease domain (residues ~268-471). No alternative well-characterized functional domain encompasses position 1471. Details ▾Hide ▴
Evidence considered
- Position 1471 is outside the exonuclease domain
- variant not listed as a hotspot or recurrent variant in León-Castillo tables.
Sources
vcep_path_250_323_s002vcep_path_250_323
PM5 No same-residue comparator variants with pathogenic or likely pathogenic classification were identified. The pm5_candidates search returned zero candidates. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variants at codon 1471 identified.
Sources
pm5_candidates
PM6 No de novo occurrence of NM_006231.4:c.4411C>T was documented in any reviewed publication or ClinVar submission. Details ▾Hide ▴
Still missing
- No de novo data available for this variant.
PP1 Although one ClinVar submitter (Invitae SCV000289377) asserted PP1 citing PMIDs 30093976 and 34897210, full-text review of PMID:30093976 confirmed the paper does not mention POLE or this variant. PMID:34897210 full text was unavailable for verification. No confirmed cosegregation data exists for this variant. Details ▾Hide ▴
Evidence considered
- Invitae SCV000289377 cites PP1 based on PMID:30093976 and PMID:34897210
- but variant-specific confirmation is absent from available full-text.
Still missing
- No verified cosegregation data.
PP2 POLE is a large gene with considerable benign missense variation in population databases. While certain missense variants in the exonuclease domain are pathogenic, PP2 requires a low rate of benign missense variation across the gene, which is not established for POLE outside the exonuclease domain. Details ▾Hide ▴
Evidence considered
- POLE has a substantial number of rare missense variants in population databases
- no gene-level constraint data supports PP2 application.
Sources
PP3 The León-Castillo et al. 2020 custom PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico results. p.Arg1471Cys is absent from both Tables S2 and S3. Generic in silico assessment: REVEL 0.334 is below the pathogenic threshold (typically 0.5); BayesDel 0.016 is in the benign range; SpliceAI max delta 0.01 predicts no splicing impact. The computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.334 (borderline/neutral)
- BayesDel 0.016 (benign)
- SpliceAI delta 0.01 (no splice impact). Variant absent from VCEP in silico tables.
Sources
PP4 No patient-specific phenotype or clinical information was provided to assess whether the variant explains a highly specific phenotype. The variant has been observed in individuals undergoing hereditary cancer testing, but clinical details are not available. Details ▾Hide ▴
Still missing
- No patient phenotype available.
PP5 ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' (7 clinical laboratories). This does not meet the 3-star expert panel threshold required for PP5 application. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 240513: VUS
- criteria provided single submitter
- 7 submitting labs
- 0 expert panel submissions.
Sources
BA1 gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both far below the >1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD AF: v2.1=0.00835%
- v4.1=0.00254%
- highest subpopulation AF=0.043% (EAS v2.1).
Sources
BS1 gnomAD v2.1 allele frequency is 0.00835% and v4.1 is 0.00254%, both below the >0.3% threshold for BS1. Details ▾Hide ▴
BS2 No homozygous observations in gnomAD (0 homozygotes across v2.1 and v4.1 combined). POLE-associated disease is autosomal dominant; observation in trans with a pathogenic variant would not apply. No healthy adult homozygous data available. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD
- 21-41 heterozygous observations.
Sources
BS3 No functional studies demonstrating a neutral effect for this variant or a systematic range including position 1471 were identified in the literature. Absence of functional data does not constitute benign functional evidence. Details ▾Hide ▴
Still missing
- No functional studies of any kind for this variant.
BS4 No segregation data is available to assess lack of cosegregation with disease. The variant has been observed in individuals with suspected hereditary cancer syndromes, but no family studies demonstrate non-segregation. Details ▾Hide ▴
Still missing
- No segregation data available.
BP1 BP1 applies when a missense variant is found in a gene where only truncating variants cause disease. POLE has established pathogenic missense variants, particularly in the exonuclease domain (P286R, V411L, S297F, A456P, S459F), indicating that missense is a known disease mechanism. Even though p.Arg1471Cys lies outside the exonuclease domain, BP1 is not appropriate for this gene. Details ▾Hide ▴
Evidence considered
- POLE exonuclease domain missense variants are a well-established disease mechanism (León-Castillo et al. 2020).
Sources
vcep_path_250_323
BP2 No observation of this variant in trans with a known pathogenic POLE variant or in a homozygous state. gnomAD reports 0 homozygotes. Details ▾Hide ▴
BP4 The León-Castillo et al. 2020 custom BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.Arg1471Cys is absent from both tables. Generic assessment: REVEL 0.334 is borderline (neither clearly pathogenic >0.5 nor clearly benign <0.2); BayesDel 0.016 is in the benign range; SpliceAI delta 0.01 predicts no splicing impact. The computational evidence is mixed and does not provide multiple lines unequivocally supporting a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.334 (borderline)
- BayesDel 0.016 (benign)
- SpliceAI 0.01 (no splice impact). Variant absent from VCEP tables.
Sources
BP5 No evidence that variants in POLE cause a disease distinct from the patient's phenotype. POLE is associated with hereditary colorectal cancer and polyposis syndromes, consistent with the clinical context in which this variant has been observed. Details ▾Hide ▴
Evidence considered
- POLE is a recognized hereditary cancer predisposition gene.
Still missing
- No patient phenotype available to assess discordance.
BP6 ClinVar classification is 'Uncertain significance' (7 clinical laboratories). No reputable source has classified this variant as benign. The review status 'criteria provided, single submitter' does not meet the 3-star expert panel threshold required for BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 240513: VUS with 7 clinical lab submissions
- no benign classification from any source.
Sources
PS5 No evidence to support PS5 application. No alternative established pathogenic variant or additional pathogenic evidence streams were identified for this variant. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.4411C>T is a missense variant (p.Arg1471Cys) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework is not applicable per pvs1_variant_assessment. Details ▾Hide ▴
Evidence considered
- Missense variant at position 1471
- not a loss-of-function null variant class.
Sources
BP7 N/ANM_006231.4:c.4411C>T is a missense variant (p.Arg1471Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.4411C>T
- Protein (HGVS p.)
- NP_006222.2:p.(Arg1471Cys)
- GRCh38
- chr12:132643440 G>A
- GRCh37
- chr12:133220026 G>A
- ClinVar
- 240513
- COSMIC
- COSV57693254
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
41 / 1,614,222 alleles
AF 2.54e-05 · 0 homozygotes · FAF 0.000153
gnomAD v2.1
21 / 251,470 alleles
AF 8.35e-05 · 0 homozygotes · FAF 0.000216
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-05 · 41 / 1,614,222 alleles · 0 hom · FAF 0.00015
| Admixed American15 / 60,034 | 0.00025 |
| East Asian11 / 44,880 | 0.00025 |
| African/African American4 / 75,058 | 5.3e-05 |
| South Asian4 / 91,082 | 4.4e-05 |
| European (non-Finnish)7 / 1,180,042 | 5.9e-06 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 8.4e-05 · 21 / 251,470 alleles · 0 hom · FAF 0.00022
| East Asian8 / 18,394 | 0.00043 |
| African/African American3 / 16,256 | 0.00018 |
| Admixed American6 / 34,592 | 0.00017 |
| Remaining individuals1 / 6,136 | 0.00016 |
| South Asian2 / 30,616 | 6.5e-05 |
| European (non-Finnish)1 / 113,754 | 8.8e-06 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.53992e-05; MAF= 0.00254%, 41/1614222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000249858; MAF= 0.02499%, 15/60034 alleles, homozygotes = 0); grpmax FAF= 0.00015347.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.3509e-05; MAF= 0.00835%, 21/251470 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434924; MAF= 0.04349%, 8/18394 alleles, homozygotes = 0); grpmax FAF= 0.00021571.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.334
- BayesDel
- 0.016
How the predictions were used
PP3 The León-Castillo et al. 2020 custom PP3 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico results. p.Arg1471Cys is absent from both Tables S2 and S3. Generic in silico assessment: REVEL 0.334 is below the pathogenic threshold (typically 0.5); BayesDel 0.016 is in the benign range; SpliceAI max delta 0.01 predicts no splicing impact. The computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.334 (borderline/neutral)
- BayesDel 0.016 (benign)
- SpliceAI delta 0.01 (no splice impact). Variant absent from VCEP in silico tables.
Sources
BP4 The León-Castillo et al. 2020 custom BP4 rule requires the variant to appear in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and ≥4 benign in silico results. p.Arg1471Cys is absent from both tables. Generic assessment: REVEL 0.334 is borderline (neither clearly pathogenic >0.5 nor clearly benign <0.2); BayesDel 0.016 is in the benign range; SpliceAI delta 0.01 predicts no splicing impact. The computational evidence is mixed and does not provide multiple lines unequivocally supporting a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.334 (borderline)
- BayesDel 0.016 (benign)
- SpliceAI 0.01 (no splice impact). Variant absent from VCEP tables.
Sources
BP7 N/ANM_006231.4:c.4411C>T is a missense variant (p.Arg1471Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = 0.0158517.
5 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
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PMID 25741868 ↗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. · 2015ACMG/AMP consensus standards and guidelines for sequence variant interpretation. NM_006231.4:c.4411C>T (p.Arg1471Cys) was not identified in this paper.Does not name this variant
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PMID 25394175 ↗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. · 2015Practice guideline from ACMG and NSGC for cancer predisposition referral indications. NM_006231.4:c.4411C>T (p.Arg1471Cys) was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc comprehensive refinement of the ACMG-AMP variant classification criteria. NM_006231.4:c.4411C>T (p.Arg1471Cys) was not identified in this paper.Does not name this variant
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PMID 30093976 ↗Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.Chan GHJ et al. · 2018Clinical genetic testing outcomes with multi-gene panel in Asian patients with multiple primary cancers. Neither POLE nor NM_006231.4:c.4411C>T was identified in the full text.Does not name this variant
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PMID 34897210 ↗Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.Park JS et al. · 2022Multigene panel testing in patients with high risk for hereditary colorectal cancer. NM_006231.4:c.4411C>T (p.Arg1471Cys) was not identified in the abstract; full text was unavailable for verification (PNG screenshot only).Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
41 / 1,614,222 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
7 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/240513/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133220026-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132643440-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132643440-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.4411…
- OncoKB ↗www.oncokb.org/gene/POLE/R1471C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126824461
- Cancer hotspots ↗www.cancerhotspots.org/
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= 2.53992e-05; MAF= 0.00254%, 41/1614222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000249858; MAF= 0.02499%, 15/60034 alleles, homozygotes = 0); grpmax FAF= 0.00015347.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.3509e-05; MAF= 0.00835%, 21/251470 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000434924; MAF= 0.04349%, 8/18394 alleles, homozygotes = 0); grpmax FAF= 0.00021571.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 240513)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = 0.0158517.
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 previously been reported in somatic cancers (COSMIC; COSV57693254, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.