About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.3959G>A, p.(Arg1320Gln)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006231.4:c.3959G>A is present at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 3.21e-05 (0.0032%, 8/249,426 alleles, 0 homozygotes; grpmax FAF=8.51e-05). In gnomAD v4.1, the frequency is 1.55e-05 (0.0016%, 25/1,613,522 alleles, 0 homozygotes; grpmax FAF=1.10e-04). Both are well below the 0.1% PM2 threshold. The variant is absent from gnomAD-Canada v1.0. Highest subpopulation frequency is in South Asians (v2.1: 0.020%, v4.1: 0.018%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Under the Leon-Castillo et al. 2020 custom POLE framework, BP4_Supporting applies when the variant appears in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and >=4 benign in silico results. R1320Q is absent from both tables, so the custom rule does not apply. Under generic fallback, multiple lines of computational evidence predict no impact: REVEL score 0.225 (below 0.5, benign-leaning), BayesDel score -0.2976 (negative, predicting benign), and SpliceAI max delta 0.02 (no splicing impact). These results support a lack of deleterious effect at the supporting evidence level.
Recorded classification: Uncertain significance
The adjudicated criteria yield exactly one pathogenic supporting criterion (PM2) and one benign supporting criterion (BP4). No pathogenic criteria reach moderate, strong, or very-strong strength, and no benign criteria reach strong or standalone strength. Under the Leon-Castillo et al. 2020 custom POLE framework (which defers to standard ACMG/AMP 2015 final-combination thresholds), the evidence is insufficient for any classification other than Uncertain Significance. Conflicting supporting-level evidence on both sides confirms VUS.
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
25 / 1,613,522 alleles
gnomAD v4.1: 25 / 1,613,522 alleles. Recorded AF 1.54941e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.20736e-05; MAF= 0.00321%, 8/249426 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196053; MAF= 0.01961%, 6/30604 alleles, homozygotes = 0); grpmax FAF= 8.513e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
5 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
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
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 · 9 not met · 12 not assessed · 3 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.3959G>A (p.Arg1320Gln) in POLE is classified as a Variant of Uncertain Significance (VUS).
This variant is a missense substitution in exon 31 of 49, located in the C-terminal region of POLE, far outside the well-characterized exonuclease domain (residues ~268-471).
The variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.0032% (8/249,426 alleles) and v4.1 allele frequency 0.0016% (25/1,613,522 alleles), with no homozygotes observed (PM2_Supporting).
Multiple in silico tools predict a benign effect: REVEL score 0.225, BayesDel score -0.2976, and SpliceAI max delta 0.02 (BP4_Supporting).
The variant is not one of the five established pathogenic POLE exonuclease-domain hotspot mutations (P286R, V411L, S297F, A456P, S459F) and is absent from the recurrent variant list in the Leon-Castillo et al. 2020 endometrial carcinoma cohort analysis.
ClinVar classifies this variant as Uncertain Significance with 5 clinical laboratory submissions and review status 'criteria provided, single submitter' (1-star). No expert panel review has been performed.
No functional studies, segregation data, de novo observations, or case-control data are available for this variant. The reviewed literature (Karbassi et al. 2016, PMID:26467025; Hampel et al. 2015, PMID:25394175; Nykamp et al. 2017, PMID:28492532) consists of variant classification methodology papers that do not mention this variant.
The net evidence balance is one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in a classification of Uncertain Significance under the ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM2 SupportingNM_006231.4:c.3959G>A is present at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 3.21e-05 (0.0032%, 8/249,426 alleles, 0 homozygotes; grpmax FAF=8.51e-05). In gnomAD v4.1, the frequency is 1.55e-05 (0.0016%, 25/1,613,522 alleles, 0 homozygotes; grpmax FAF=1.10e-04). Both are well below the 0.1% PM2 threshold. The variant is absent from gnomAD-Canada v1.0. Highest subpopulation frequency is in South Asians (v2.1: 0.020%, v4.1: 0.018%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=3.21e-05 (0.0032%)
- 8/249
- 426 alleles
- 0 homozygotes.
- gnomAD v4.1 AF=1.55e-05 (0.0016%)
- 25/1
- 613
- 522 alleles
- gnomAD-Canada: absent.
- Both v2.1 and v4.1 AF well below PM2 threshold of 0.1%.
Sources
BP4 SupportingUnder the Leon-Castillo et al. 2020 custom POLE framework, BP4_Supporting applies when the variant appears in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and >=4 benign in silico results. R1320Q is absent from both tables, so the custom rule does not apply. Under generic fallback, multiple lines of computational evidence predict no impact: REVEL score 0.225 (below 0.5, benign-leaning), BayesDel score -0.2976 (negative, predicting benign), and SpliceAI max delta 0.02 (no splicing impact). These results support a lack of deleterious effect at the supporting evidence level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.225 (below pathogenic threshold
- benign-leaning).
- BayesDel score: -0.2976 (negative
- predicting benign).
- SpliceAI max delta: 0.02 (no predicted splicing impact).
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No functional data exist for NM_006231.4:c.3959G>A or a systematically characterized range that includes position 1320. The variant is absent from OncoKB curated functional evidence and is not in COSMIC. The variant lies outside the well-characterized exonuclease domain (residues ~268-471), and no experimental studies have tested this variant or a saturation mutagenesis range covering residue 1320. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect with no variant-specific functional evidence.
- COSMIC: variant not found in somatic cancer database.
- Position 1320 is C-terminal
- outside the exonuclease domain characterized by Leon-Castillo et al. 2020.
Still missing
- No published functional studies for this variant or a systematically characterized range spanning residue 1320.
Sources
PS4 Under the Leon-Castillo et al. 2020 custom POLE framework, PS4_Supporting applies only when the exact missense variant is recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined EC count >=10. NM_006231.4:c.3959G>A (p.Arg1320Gln) is absent from Supplementary Table S1 and is not one of the established pathogenic hotspots. No germline case-control evidence is available to support generic PS4 application. Details ▾Hide ▴
Evidence considered
- R1320Q is absent from Leon-Castillo Supplementary Table S1 (recurrent POLE variants in EC).
- Variant is not found in COSMIC.
- No germline case-control or prevalence data available.
Still missing
- No somatic recurrence in EC cohorts.
- No germline case-control data.
Sources
PM1 Under the Leon-Castillo et al. 2020 custom POLE framework, PM1 applies only to specified exonuclease-domain hotspot and recurrent variants. p.Arg1320Gln lies at the C-terminus of POLE, far outside the exonuclease domain (residues ~268-471), and is not one of the five established pathogenic hotspots (P286R, V411L, S297F, A456P, S459F) or the listed recurrent non-hotspot variants. No other well-characterized critical functional domain has been described at position 1320. Details ▾Hide ▴
Evidence considered
- R1320Q is located at the C-terminus
- outside the exonuclease domain (residues ~268-471).
- Not among the five established pathogenic hotspots or the six listed recurrent non-hotspot variants in the Leon-Castillo framework.
- No critical functional domain characterized at position 1320.
Sources
PP3 Under the Leon-Castillo et al. 2020 custom POLE framework, PP3_Supporting applies only when the exact missense variant appears in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and <=1 benign in silico results. R1320Q is absent from both supplementary tables, so the custom rule does not apply. Under generic fallback, multiple lines of computational evidence predict a benign effect: REVEL score 0.225 (below the 0.5 pathogenic threshold), BayesDel score -0.2976 (negative = benign), and SpliceAI max delta 0.02 (no splicing impact). These results do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- R1320Q is absent from Leon-Castillo Supplementary Tables S2 and S3.
- REVEL score: 0.225 (below pathogenic threshold of 0.5).
- BayesDel score: -0.2976 (negative
- predicting benign).
- SpliceAI max delta: 0.02 (no predicted splicing impact).
Sources
PP5 ClinVar reports this variant as Uncertain Significance with review status 'criteria provided, single submitter' (1-star). The PP5/BP6 rule requires a 3-star expert panel review for supporting-level application. No expert panel has reviewed this variant, and the single submitter classification does not meet the threshold for PP5. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance.
- Review status: criteria provided
- single submitter (1-star).
- No expert panel submission
- 0 expert panel reviews.
- Does not meet 3-star threshold for PP5.
Sources
BA1 The variant is present at very low frequency in gnomAD. v2.1 AF=3.21e-05 (0.0032%), v4.1 AF=1.55e-05 (0.0016%). Both are well below the 1% BA1 threshold. The highest subpopulation frequency is 0.020% in South Asians (v2.1), also far below 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0032%
- v4.1 AF=0.0016% — both <<1% BA1 threshold.
- Highest subpopulation AF=0.020% (South Asian
- v2.1) — also <<1%.
Sources
BS1 The variant is present at very low frequency in gnomAD. v2.1 AF=3.21e-05 (0.0032%), v4.1 AF=1.55e-05 (0.0016%). Both are well below the 0.3% BS1 threshold. The highest subpopulation frequency is 0.020% in South Asians (v2.1), also far below 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0032%
- v4.1 AF=0.0016% — both <<0.3% BS1 threshold.
- Highest subpopulation AF=0.020% (South Asian
- v2.1) — also <<0.3%.
Sources
BP1 BP1 is not met. BP1 applies when a missense variant occurs in a gene where only truncating variants are known to cause disease. POLE has well-established pathogenic missense variants, particularly in the exonuclease domain (e.g., P286R, V411L, S297F, A456P, S459F), which cause ultramutated phenotype in endometrial carcinoma. Therefore, POLE does not meet the BP1 requirement that only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- POLE has established pathogenic missense variants in the exonuclease domain.
- BP1 requires that only truncating variants cause disease in the gene.
Sources
vcep_path_250_323
BP6 ClinVar reports this variant as Uncertain Significance with review status 'criteria provided, single submitter' (1-star). The PP5/BP6 rule requires a 3-star expert panel review for supporting-level application. No expert panel has reviewed this variant, and the current classification does not support a benign assertion through BP6. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance.
- Review status: criteria provided
- single submitter (1-star).
- No expert panel submission.
- Does not meet 3-star threshold for BP6.
Sources
Not assessed · 12 · no assessment recorded
PS1 No evidence is available regarding a different pathogenic nucleotide change at the same amino acid position (Arg1320). No literature or database entries describe a pathogenic missense change at codon 1320 with a different nucleotide substitution. Details ▾Hide ▴
Still missing
- No known pathogenic variant at codon 1320 with a different nucleotide change was identified.
PS2 No de novo data are available for this variant. No published reports of de novo occurrence were identified in ClinVar submissions or the reviewed literature. Details ▾Hide ▴
Still missing
- No de novo observations reported.
PM6 No de novo data are available for this variant. No published reports of de novo occurrence were identified. Details ▾Hide ▴
Still missing
- No de novo observations reported.
PP1 No segregation data are available for this variant. No family studies or co-segregation analyses were identified in ClinVar or the reviewed literature. Details ▾Hide ▴
Still missing
- No segregation data available.
PP2 PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. While POLE exonuclease domain missense variants are a known disease mechanism, the variant at position 1320 lies outside this domain. Insufficient gene-level missense constraint data are available to confidently apply PP2 across the entire POLE coding sequence. Details ▾Hide ▴
Evidence considered
- POLE exonuclease domain missense variants are a recognized disease mechanism.
- R1320Q lies outside the exonuclease domain in the C-terminal region.
- Insufficient constraint data for PP2 application across full POLE sequence.
Still missing
- No gene-level missense constraint Z-score or benign missense rate data for POLE evaluated.
PP4 No patient phenotype or family history data are provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Still missing
- No phenotype or family history data available for assessment.
BS2 No data are available regarding homozygous or hemizygous observations of this variant in healthy individuals. BS2 requires observation in a homozygous or hemizygous state without disease. Details ▾Hide ▴
Still missing
- No homozygous or hemizygous observations reported in healthy individuals.
BS3 No functional studies have been performed on this variant to demonstrate a benign effect. While in silico tools predict a benign outcome (REVEL 0.225, BayesDel -0.298), these are computational predictions (BP4 territory), not experimental functional evidence meeting BS3 standards. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional assays have tested this variant.
- In silico predictions suggesting benign effect are captured under BP4.
Still missing
- No experimental functional studies demonstrating no damaging effect.
BS4 No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 No data are available regarding observations of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant in a gene for which fully penetrant dominant disease is the established mechanism. Details ▾Hide ▴
Still missing
- No in trans observations reported.
BP5 No data are available regarding an alternate molecular basis for disease in this case. BP5 requires that an alternate cause of disease has been identified. Details ▾Hide ▴
Still missing
- No alternate molecular basis identified.
PS5 No data are available to support PS5. This criterion requires a different pathogenic variant at the same codon, supported by functional or clinical evidence independent of PM5. No such evidence was identified for codon 1320. Details ▾Hide ▴
Still missing
- No pathogenic variant at codon 1320 supported by independent evidence.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable. NM_006231.4:c.3959G>A is a missense substitution (p.Arg1320Gln) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical +/-1,2 splice consensus). The variant lies in exon 31 of 49, outside the exonuclease domain, and the ClinGen SVI PVS1 framework does not support PVS1 for missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.3959G>A (p.Arg1320Gln)
- not a predicted null variant.
- ClinGen SVI PVS1 decision tree does not apply to missense variants.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/APM5 cannot be applied. The automated PM5 candidate harvesting pipeline was unable to identify same-residue comparator variants for position Arg1320. No ClinVar entries describe a different pathogenic missense change at this codon. Details ▾Hide ▴
Evidence considered
- No same-residue comparator variants identified at Arg1320.
- PM5 candidate pipeline returned 0 candidates.
Sources
pm5_candidates
BP7 N/ABP7 applies to silent/intronic variants outside the splice consensus. NM_006231.4:c.3959G>A is a missense variant (p.Arg1320Gln), not a silent or intronic change. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a silent or intronic variant.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.3959G>A
- Protein (HGVS p.)
- NP_006222.2:p.(Arg1320Gln)
- GRCh38
- chr12:132649352 C>T
- GRCh37
- chr12:133225938 C>T
- ClinVar
- 240494
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
25 / 1,613,522 alleles
AF 1.55e-05 · 0 homozygotes · FAF 0.00011
gnomAD v2.1
8 / 249,426 alleles
AF 3.21e-05 · 0 homozygotes · FAF 8.51e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 25 / 1,613,522 alleles · 0 hom · FAF 0.00011
| South Asian16 / 91,092 | 0.00018 |
| Middle Eastern1 / 6,084 | 0.00016 |
| Remaining individuals3 / 62,486 | 4.8e-05 |
| African/African American1 / 74,950 | 1.3e-05 |
| European (non-Finnish)4 / 1,180,050 | 3.4e-06 |
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 8 / 249,426 alleles · 0 hom · FAF 8.5e-05
| South Asian6 / 30,604 | 0.0002 |
| Remaining individuals1 / 6,108 | 0.00016 |
| European (non-Finnish)1 / 112,312 | 8.9e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.54941e-05; MAF= 0.00155%, 25/1613522 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000175647; MAF= 0.01756%, 16/91092 alleles, homozygotes = 0); grpmax FAF= 0.00010969.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.20736e-05; MAF= 0.00321%, 8/249426 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196053; MAF= 0.01961%, 6/30604 alleles, homozygotes = 0); grpmax FAF= 8.513e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.225
- BayesDel
- -0.298
How the predictions were used
BP4 SupportingUnder the Leon-Castillo et al. 2020 custom POLE framework, BP4_Supporting applies when the variant appears in Supplementary Table S2 or S3 with REVEL class 'Likely benign' and >=4 benign in silico results. R1320Q is absent from both tables, so the custom rule does not apply. Under generic fallback, multiple lines of computational evidence predict no impact: REVEL score 0.225 (below 0.5, benign-leaning), BayesDel score -0.2976 (negative, predicting benign), and SpliceAI max delta 0.02 (no splicing impact). These results support a lack of deleterious effect at the supporting evidence level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.225 (below pathogenic threshold
- benign-leaning).
- BayesDel score: -0.2976 (negative
- predicting benign).
- SpliceAI max delta: 0.02 (no predicted splicing impact).
Sources
PP3 Under the Leon-Castillo et al. 2020 custom POLE framework, PP3_Supporting applies only when the exact missense variant appears in Supplementary Table S2 or S3 with REVEL class 'likely disease causing' and <=1 benign in silico results. R1320Q is absent from both supplementary tables, so the custom rule does not apply. Under generic fallback, multiple lines of computational evidence predict a benign effect: REVEL score 0.225 (below the 0.5 pathogenic threshold), BayesDel score -0.2976 (negative = benign), and SpliceAI max delta 0.02 (no splicing impact). These results do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- R1320Q is absent from Leon-Castillo Supplementary Tables S2 and S3.
- REVEL score: 0.225 (below pathogenic threshold of 0.5).
- BayesDel score: -0.2976 (negative
- predicting benign).
- SpliceAI max delta: 0.02 (no predicted splicing impact).
Sources
BP7 N/ABP7 applies to silent/intronic variants outside the splice consensus. NM_006231.4:c.3959G>A is a missense variant (p.Arg1320Gln), not a silent or intronic change. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a silent or intronic variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.225. BayesDel score = -0.297636.
2 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
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a standardized rules-based DNA variant scoring system for pathogenicity assessment in Mendelian disorders. This is a variant classification methodology paper — NM_006231.4:c.3959G>A was not identified in this publication.Does not name this variant
-
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. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. This is a clinical practice guideline — NM_006231.4:c.3959G>A was not identified in this publication.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
25 / 1,613,522 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
5 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/240494/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133225938-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132649352-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132649352-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.3959…
- OncoKB ↗www.oncokb.org/gene/POLE/R1320Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.3959G%3EA
- 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= 1.54941e-05; MAF= 0.00155%, 25/1613522 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000175647; MAF= 0.01756%, 16/91092 alleles, homozygotes = 0); grpmax FAF= 0.00010969.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.20736e-05; MAF= 0.00321%, 8/249426 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196053; MAF= 0.01961%, 6/30604 alleles, homozygotes = 0); grpmax FAF= 8.513e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 240494)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.225. BayesDel score = -0.297636.
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.