About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.6766G>A, p.(Gly2256Arg)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
The gnomAD grpmax filtering allele frequency (FAF) is 1.22% in v2.1 and 1.29% in v4.1, exceeding the 1% BA1 threshold. The African/African American subpopulation allele frequency is 1.35% in both gnomAD versions, with 4 homozygotes in v2.1 and 8 homozygotes in v4.1. This population frequency far exceeds what would be expected for a pathogenic variant in POLE-associated disorders.
BS1Strong
BS1 · strong
The gnomAD population allele frequency exceeds the 0.3% BS1 threshold. The grpmax FAF is 1.22% (v2.1) and 1.29% (v4.1), and the African/African American subpopulation frequency is 1.35%. This is substantially greater than expected for a pathogenic variant in POLE-associated hereditary cancer syndromes and is superseded by the BA1 criterion.
BS2Strong
BS2 · strong
The variant is observed in the homozygous state in gnomAD population databases: 4 homozygotes in v2.1 (exomes + genomes, primarily in African/African American population) and 8 homozygotes in v4.1. Observation of homozygosity for a variant in a gene where pathogenic variants are associated with an autosomal dominant cancer predisposition syndrome (POLE-associated colorectal and endometrial cancer) constitutes strong evidence for a benign effect, as homozygous loss of function would be expected to be lethal or cause severe early-onset disease.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict a benign effect. REVEL score is 0.048 (benign), BayesDel score is -0.759 (strongly benign), and SpliceAI delta score is 0.01 (no predicted splicing impact). The variant is absent from the León-Castillo et al. supplementary tables, so the custom POLE BP4 rule is not triggered; the generic in silico assessment applies. All available computational tools agree on a benign prediction.
Recorded classification: Benign
BA1 (stand-alone benign) is met: gnomAD grpmax filtering allele frequency of 1.22% (v2.1) / 1.29% (v4.1) exceeds the 1% BA1 threshold, with 4–8 homozygotes observed. BA1 alone is sufficient for Benign classification under both the local custom POLE framework (León-Castillo et al. 2020) and generic ACMG/AMP 2015 rules. Additional criteria BS1 (strong benign, AF >0.3%), BS2 (strong benign, homozygotes in population), and BP4 (supporting benign, concordant in silico benign predictions) provide further supportive evidence.
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
1,166 / 1,612,714 alleles
gnomAD v4.1: 1,166 / 1,612,714 alleles. Recorded AF 0.000723005. Recorded homozygote count 8.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00127346; MAF= 0.12735%, 359/281910 alleles, homozygotes = 4) and has highest observed frequency in the African/African American population (AF= 0.0134745; MAF= 1.34745%, 336/24936 alleles, homozygotes = 4); grpmax FAF= 0.0121994.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971769815418024, 11/18420 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
10 reported laboratory submissions
9 Benign · 1 Likely benign. 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: 4 met · 20 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.6766G>A (p.Gly2256Arg) meets BA1 (stand-alone benign) based on gnomAD grpmax filtering allele frequency of 1.22% in v2.1 and 1.29% in v4.1, exceeding the 1% BA1 threshold, with 4–8 homozygotes observed across datasets.
The variant meets BS1 (strong benign) with a grpmax allele frequency of 1.22% in gnomAD and an African/African American subpopulation frequency of 1.35%, far exceeding the 0.3% BS1 threshold for a disorder with this prevalence.
The variant meets BS2 (strong benign): 4 homozygotes are observed in gnomAD v2.1 and 8 homozygotes in gnomAD v4.1, all in the African/African American population, which is incompatible with a fully penetrant autosomal dominant cancer predisposition syndrome.
The variant meets BP4 (supporting benign): multiple computational tools concordantly predict a benign effect (REVEL 0.048, BayesDel -0.759, SpliceAI delta 0.01).
The variant is absent from the León-Castillo et al. 2020 POLE recurrent variant tables (Supplementary Tables S1–S3), is not in COSMIC, and lies in the C-terminal region (position 2256) outside the exonuclease domain (residues 268–471), so the custom POLE PM1, PS4, and PP3 criteria do not apply.
BA1 alone is sufficient for a Benign classification per ACMG/AMP 2015 combination rules. The additional BS1, BS2, and BP4 criteria provide further supportive benign evidence.
No criteria match.
Met · 4
BA1 Stand aloneThe gnomAD grpmax filtering allele frequency (FAF) is 1.22% in v2.1 and 1.29% in v4.1, exceeding the 1% BA1 threshold. The African/African American subpopulation allele frequency is 1.35% in both gnomAD versions, with 4 homozygotes in v2.1 and 8 homozygotes in v4.1. This population frequency far exceeds what would be expected for a pathogenic variant in POLE-associated disorders. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF = 1.22% (>1% BA1 threshold)
- gnomAD v4.1 grpmax FAF = 1.29%
- African/African American AF = 1.35%
- 4 homozygotes in v2.1
- 8 homozygotes in v4.1
Sources
BS1 StrongThe gnomAD population allele frequency exceeds the 0.3% BS1 threshold. The grpmax FAF is 1.22% (v2.1) and 1.29% (v4.1), and the African/African American subpopulation frequency is 1.35%. This is substantially greater than expected for a pathogenic variant in POLE-associated hereditary cancer syndromes and is superseded by the BA1 criterion. Details ▾Hide ▴
Evidence considered
- gnomAD grpmax FAF = 1.22% (>0.3% BS1 threshold)
- African/African American subpopulation AF = 1.35%
Sources
BS2 StrongThe variant is observed in the homozygous state in gnomAD population databases: 4 homozygotes in v2.1 (exomes + genomes, primarily in African/African American population) and 8 homozygotes in v4.1. Observation of homozygosity for a variant in a gene where pathogenic variants are associated with an autosomal dominant cancer predisposition syndrome (POLE-associated colorectal and endometrial cancer) constitutes strong evidence for a benign effect, as homozygous loss of function would be expected to be lethal or cause severe early-onset disease. Details ▾Hide ▴
Evidence considered
- 4 homozygotes in gnomAD v2.1 (exomes + genomes)
- 8 homozygotes in gnomAD v4.1
- All homozygotes found in African/African American population
Sources
BP4 SupportingMultiple lines of computational evidence predict a benign effect. REVEL score is 0.048 (benign), BayesDel score is -0.759 (strongly benign), and SpliceAI delta score is 0.01 (no predicted splicing impact). The variant is absent from the León-Castillo et al. supplementary tables, so the custom POLE BP4 rule is not triggered; the generic in silico assessment applies. All available computational tools agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.048 (benign range)
- BayesDel score = -0.759 (strongly benign)
- SpliceAI max delta = 0.01 (no splice impact)
- Multiple concordant benign predictions across independent tools
Sources
Not met · 20 · evaluated, threshold not reached
PVS1 NM_006231.4:c.6766G>A is a missense variant (p.Gly2256Arg) in exon 49 of POLE. It does not fall into the null-variant categories (nonsense, frameshift, canonical ±1,2 splice) required for PVS1 application under the ClinGen SVI PVS1 decision tree (PMC6185798). PVS1 is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution (c.6766G>A
- p.Gly2256Arg) in exon 49
- Not a nonsense
- frameshift
- or canonical splice variant
- ClinGen SVI PVS1 framework does not support PVS1 for missense variants
Sources
PS1 No evidence of a different nucleotide change at codon 2256 producing the same p.Gly2256Arg missense change that is established as pathogenic. No same-codon comparator variants were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 2256 identified as pathogenic
Still missing
- No same-codon nucleotide change data available
PS2 No de novo occurrence data available for this variant. No published reports of de novo POLE c.6766G>A were identified. Details ▾Hide ▴
Evidence considered
- No de novo data found in ClinVar submissions or literature
Still missing
- No parental testing or de novo reports available
PS3 No variant-specific functional studies were identified for NM_006231.4:c.6766G>A (p.Gly2256Arg). The variant is absent from the León-Castillo et al. 2020 supplementary tables and is not listed in OncoKB with reviewed functional evidence. Position 2256 lies in the C-terminal region of POLE, far outside the exonuclease domain (residues 268–471), and no functional characterization of this region or variant was found. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence
- Variant absent from León-Castillo et al. 2020 supplementary tables (S1
- S2
- S3)
- Position 2256 is C-terminal
- outside the exonuclease domain (268–471)
Still missing
- No functional studies of this variant or systematically characterized range including position 2256
Sources
oncokb ↗vcep_path_250_323
PS4 The variant does not meet the custom POLE framework PS4_Supporting criteria: it is absent from the León-Castillo et al. Supplementary Table S1 (recurrent variants in COSMIC/TCGA endometrial carcinoma cohorts), not present in COSMIC, and does not belong to the established pathogenic hotspot set. No germline case-control data are available. The custom framework PS4_Supporting requires exact-variant recurrence in both COSMIC and TCGA with combined EC count ≥10, which this variant does not satisfy. Details ▾Hide ▴
Evidence considered
- Variant absent from COSMIC
- Variant absent from Supplementary Table S1 (POLE recurrent variants in EC)
- No germline case-control data
- Custom POLE PS4 rule requires recurrence in both COSMIC and TCGA cohorts
Still missing
- No case-control or cohort enrichment data
Sources
vcep_path_250_323_s002clinvar ↗
PM1 The variant does not meet any tier of the custom POLE PM1 framework. It is not one of the five established exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F), not one of the non-hotspot recurrent pathogenic variants (F367S, L424I, M295R, P436R, M444K, D368Y), and not in the uncertain-tier set (A465V, L424V, T278M, A428T). Position 2256 is in the C-terminal region, far from the exonuclease domain (residues 268–471). Cancerhotspots.org does not identify this as a significant hotspot residue. No functional domain at position 2256 has been characterized as critical in the literature. Details ▾Hide ▴
Evidence considered
- Position 2256 is C-terminal
- not in exonuclease domain (268–471)
- Not one of the five hotspot variants per León-Castillo et al. 2020
- Not listed as recurrent in Supplementary Table S1
- Not a significant hotspot residue per cancerhotspots.org
Sources
vcep_path_250_323vcep_path_250_323_s002
PM2 gnomAD v2.1 total allele frequency is 0.127% (359/281,910 alleles), exceeding the 0.1% PM2 threshold. gnomAD v4.1 total frequency is 0.072% (1,166/1,612,714 alleles). The variant is present at appreciable frequency in population databases, particularly in the African/African American population (1.347% in v2.1, 1.358% in v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF = 0.127% (>0.1% PM2 threshold)
- gnomAD v4.1 total AF = 0.072%
- African/African American AF = 1.35%
- 4 homozygotes in v2.1
- 8 homozygotes in v4.1
Sources
PM5 No same-residue comparator variants were identified for PM5 assessment. The automated PM5 candidate harvest found zero candidates at codon 2256. No alternative pathogenic missense change at the same amino acid position is known. Details ▾Hide ▴
Evidence considered
- Zero PM5 candidates identified at codon 2256
- Automated PM5 candidate harvesting returned no results
Still missing
- No same-residue comparator variants exist in available databases
Sources
pm5_candidates
PM6 No de novo occurrence data available for this variant. No published reports of a de novo POLE c.6766G>A event were identified in the literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar submissions
- No de novo reports in literature
Still missing
- No parental testing or de novo data
PP1 No segregation data are available for this variant. No published family studies or co-segregation analyses involving NM_006231.4:c.6766G>A were identified. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar submissions or literature
Still missing
- No family segregation data available
PP2 PP2 requires that missense variants are a common disease mechanism in the gene AND benign missense variation is low. While pathogenic POLE missense variants in the exonuclease domain are a known mechanism, the C-terminal region (position 2256) tolerates substantial benign missense variation: this variant itself is present at 0.13% overall and 1.35% in the African population with homozygotes, indicating high tolerance of missense changes in this region. PP2 does not apply. Details ▾Hide ▴
Evidence considered
- Variant present at 0.13% in gnomAD v2.1 with 4 homozygotes
- African subpopulation AF = 1.35% with 4–8 homozygotes across datasets
- C-terminal region tolerates missense variation
Sources
PP3 The variant is absent from the León-Castillo et al. Supplementary Tables S2 and S3, so the custom POLE PP3_Supporting rule does not apply. Falling back to generic in silico assessment: REVEL score is 0.048 (benign-leaning), BayesDel score is -0.759 (strongly benign), and SpliceAI delta score is 0.01 (no splice impact). Multiple lines of computational evidence predict a benign effect, contradicting PP3 application. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.048 (benign)
- BayesDel score = -0.759 (benign)
- SpliceAI max delta = 0.01 (no splice impact)
- Variant absent from Supplementary Tables S2 and S3
Sources
PP4 No patient phenotype data are available for this case. PP4 requires that the variant is identified in a patient with a phenotype highly specific for the gene/disease, which cannot be assessed without clinical phenotype information. Details ▾Hide ▴
Evidence considered
- No patient phenotype provided for case
Still missing
- No patient phenotype data available
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect of NM_006231.4:c.6766G>A were identified. In silico predictions alone do not satisfy BS3 requirements. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant
Still missing
- No functional studies of this variant
BS4 No segregation data are available. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No segregation analysis data
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. For POLE, the established pathogenic mechanism includes missense variants in the exonuclease domain (e.g., P286R, V411L, S297F, A456P, S459F). Missense variants are a recognized disease mechanism for POLE, so BP1 does not apply even though this specific variant falls outside the exonuclease domain. Details ▾Hide ▴
Evidence considered
- POLE pathogenic variants are predominantly missense in the exonuclease domain
- Missense is a known disease mechanism for POLE
Sources
vcep_path_250_323
BP2 No evidence that this variant has been observed in trans with a known pathogenic POLE variant. The gnomAD homozygote observations are in population controls, not in the context of a confirmed pathogenic variant in trans. Details ▾Hide ▴
Evidence considered
- No trans-configuration data with a known pathogenic variant
Still missing
- No co-occurrence data with pathogenic variants
BP5 No alternative molecular cause for the patient's phenotype has been identified. BP5 requires that an alternative cause is found, which is not documented for this case. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis documented
Still missing
- No data on alternative molecular causes
BP6 While ClinVar reports this variant as Benign by 9 clinical laboratories and Likely benign by 1 laboratory, the aggregate review status is 1-star (criteria provided, single submitter), not 3-star expert panel. Under the adjudication framework, BP6 at supporting strength requires ClinVar 3-star expert panel status. The 1-star review status does not meet this threshold for formal BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar classification = Benign (9 labs)
- Likely benign (1 lab)
- Review status = criteria provided
- single submitter (1-star)
- Does not meet 3-star expert panel threshold for BP6
Sources
PS5 No alternative pathogenic missense variant at codon 2256 of POLE has been identified. No ClinVar entries or literature reports describe a different missense change at this codon classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No pathogenic variant at codon 2256 in ClinVar
- p.Gly2256Arg is the only reported variant at this codon
Still missing
- No same-codon comparator data
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PP5 N/APP5 requires a reputable source reporting the variant as pathogenic. ClinVar classification for this variant is Benign (9 clinical laboratories) and Likely benign (1 clinical laboratory). With a benign classification, PP5 is not applicable. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. NM_006231.4:c.6766G>A is a missense variant (p.Gly2256Arg), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly2256Arg)
- not synonymous
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.6766G>A
- Protein (HGVS p.)
- NP_006222.2:p.(Gly2256Arg)
- GRCh38
- chr12:132624792 C>T
- GRCh37
- chr12:133201378 C>T
- ClinVar
- 381926
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
1,166 / 1,612,714 alleles
AF 0.000723 · 8 homozygotes · FAF 0.0129
gnomAD v2.1
359 / 281,910 alleles
AF 0.00127 · 4 homozygotes · FAF 0.0122
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00072 · 1166 / 1,612,714 alleles · 8 hom · FAF 0.013
| African/African American1019 / 75,012 | 0.0148 hom |
| Remaining individuals60 / 62,474 | 0.00096 |
| Admixed American45 / 60,036 | 0.00075 |
| Middle Eastern3 / 6,062 | 0.00049 |
| East Asian3 / 44,888 | 6.7e-05 |
| South Asian6 / 91,060 | 6.6e-05 |
| European (non-Finnish)30 / 1,178,650 | 2.5e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0013 · 359 / 281,910 alleles · 4 hom · FAF 0.012
| African/African American336 / 24,936 | 0.0134 hom |
| Admixed American17 / 35,436 | 0.00048 |
| Remaining individuals2 / 7,220 | 0.00028 |
| East Asian3 / 19,952 | 0.00015 |
| European (non-Finnish)1 / 128,270 | 7.8e-06 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, European (Finnish), South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000723005; MAF= 0.07230%, 1166/1612714 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0135845; MAF= 1.35845%, 1019/75012 alleles, homozygotes = 8); grpmax FAF= 0.0128916.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00127346; MAF= 0.12735%, 359/281910 alleles, homozygotes = 4) and has highest observed frequency in the African/African American population (AF= 0.0134745; MAF= 1.34745%, 336/24936 alleles, homozygotes = 4); grpmax FAF= 0.0121994.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971769815418024, 11/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.048
- BayesDel
- -0.759
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict a benign effect. REVEL score is 0.048 (benign), BayesDel score is -0.759 (strongly benign), and SpliceAI delta score is 0.01 (no predicted splicing impact). The variant is absent from the León-Castillo et al. supplementary tables, so the custom POLE BP4 rule is not triggered; the generic in silico assessment applies. All available computational tools agree on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.048 (benign range)
- BayesDel score = -0.759 (strongly benign)
- SpliceAI max delta = 0.01 (no splice impact)
- Multiple concordant benign predictions across independent tools
Sources
PP3 The variant is absent from the León-Castillo et al. Supplementary Tables S2 and S3, so the custom POLE PP3_Supporting rule does not apply. Falling back to generic in silico assessment: REVEL score is 0.048 (benign-leaning), BayesDel score is -0.759 (strongly benign), and SpliceAI delta score is 0.01 (no splice impact). Multiple lines of computational evidence predict a benign effect, contradicting PP3 application. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.048 (benign)
- BayesDel score = -0.759 (benign)
- SpliceAI max delta = 0.01 (no splice impact)
- Variant absent from Supplementary Tables S2 and S3
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. NM_006231.4:c.6766G>A is a missense variant (p.Gly2256Arg), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly2256Arg)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.048. BayesDel score = -0.758792.
6 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 2015 standards and guidelines for interpretation of sequence variants. This is a methodological consensus paper describing the variant classification framework; it does not discuss individual POLE variants.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a standardized DNA variant scoring system for pathogenicity assessments in Mendelian disorders. A methodological paper; does not discuss individual POLE variants.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. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. A clinical practice guideline; does not discuss individual POLE variants.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics risk assessment and counseling summary. A health professional summary; does not discuss individual POLE variants.Does not name this variant
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PMID 26389505 ↗Genetics of Colorectal Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ genetics of colorectal cancer summary. A health professional summary; does not discuss individual POLE variants.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 ACMG-AMP variant classification criteria. A methodological paper; does not discuss individual POLE variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,166 / 1,612,714 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
9 Benign · 1 Likely benign
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/381926/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133201378-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132624792-C-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132624792-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.6766…
- OncoKB ↗www.oncokb.org/gene/POLE/G2256R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.6766G%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= 0.000723005; MAF= 0.07230%, 1166/1612714 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0135845; MAF= 1.35845%, 1019/75012 alleles, homozygotes = 8); grpmax FAF= 0.0128916.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00127346; MAF= 0.12735%, 359/281910 alleles, homozygotes = 4) and has highest observed frequency in the African/African American population (AF= 0.0134745; MAF= 1.34745%, 336/24936 alleles, homozygotes = 4); grpmax FAF= 0.0121994.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005971769815418024, 11/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 381926)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.048. BayesDel score = -0.758792.
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.