About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.1270C>A, p.(Leu424Ile)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM1Moderate
PM1 · moderate
p.Leu424Ile is explicitly listed in the León-Castillo et al. 2020 custom POLE framework as a non-hotspot exonuclease-domain missense variant qualifying for PM1_Moderate. The variant falls within the exonuclease proofreading domain (residues 268-471) and was classified in the pathogenic tier (POLE-score >=4) in the TCGA-based analysis.
PM2Moderate
PM2 · moderate
NM_006231.4:c.1270C>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold of allele frequency <0.1%.
PM5Moderate
PM5 · moderate
A different pathogenic missense variant at the same codon — c.1270C>G (p.Leu424Val) — is established as a high-penetrance germline pathogenic variant causing polymerase proofreading-associated polyposis (PPAP), confirmed across multiple independent cohorts (Palles et al. 2013, Valle et al. 2014, Elsayed et al. 2014, Spier et al. 2015). The novel c.1270C>A (p.Leu424Ile) substitution at the same residue therefore meets PM5 at moderate strength.
PP3Supporting
PP3 · supporting
p.L424I appears in Supplementary Table S2 of León-Castillo et al. 2020 with REVEL class 'likely disease causing' and only 1 benign in silico result (<=1), meeting the custom POLE PP3_Supporting rule. SpliceAI predicts no splicing impact (max delta score = 0.00).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Three moderate-strength pathogenic criteria are met (PM1, PM2, PM5) with one additional supporting criterion (PP3). The León-Castillo et al. 2020 custom POLE framework was used for criterion triggering and strength selection, but the framework explicitly retains standard ACMG/AMP 2015 final-combination thresholds. Under the standard ACMG/AMP combination rules, >=3 moderate criteria alone qualifies as Likely Pathogenic. No benign criteria are met, so there is no conflicting 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57691098, n = 2 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: 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
p.Leu424Ile is an exonuclease-domain missense variant explicitly assigned PM1 at moderate strength in the León-Castillo et al. 2020 custom POLE framework based on recurrence in the TCGA endometrial carcinoma cohort (n=2) and classification in the pathogenic POLE-score tier.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting the PM2 threshold of <0.1% allele frequency.
A different pathogenic missense variant at the same codon, c.1270C>G (p.Leu424Val), is established as a high-penetrance germline cause of polymerase proofreading-associated polyposis across multiple independent cohorts (Palles et al. 2013, Valle et al. 2014, Elsayed et al. 2014, Spier et al. 2015), satisfying PM5 at moderate strength.
In silico assessment from Supplementary Table S2 shows REVEL class 'likely disease causing' with only 1 benign result (SIFT=Deleterious, PANTHER=Probably damaging, SNAP2=effect, PolyPhen2=Probably damaging, PROVEAN=Neutral), meeting the custom POLE PP3_Supporting rule.
No variant-specific functional data, de novo observations, segregation data, or germline case-control evidence exist for c.1270C>A; eight publications citing POLE codon 424 all refer to the sister variant c.1270C>G (p.Leu424Val) and do not mention c.1270C>A.
No criteria match.
Met · 4
PM1 Moderatep.Leu424Ile is explicitly listed in the León-Castillo et al. 2020 custom POLE framework as a non-hotspot exonuclease-domain missense variant qualifying for PM1_Moderate. The variant falls within the exonuclease proofreading domain (residues 268-471) and was classified in the pathogenic tier (POLE-score >=4) in the TCGA-based analysis. Details ▾Hide ▴
Evidence considered
- León-Castillo et al. 2020 framework explicitly assigns PM1_Moderate to p.L424I
- variant is in the exonuclease domain and recurrent in TCGA EC cohort (n=2).
Sources
vcep_path_250_323vcep_path_250_323_s002
PM2 ModerateNM_006231.4:c.1270C>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold of allele frequency <0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- gnomAD v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes).
Sources
PM5 ModerateA different pathogenic missense variant at the same codon — c.1270C>G (p.Leu424Val) — is established as a high-penetrance germline pathogenic variant causing polymerase proofreading-associated polyposis (PPAP), confirmed across multiple independent cohorts (Palles et al. 2013, Valle et al. 2014, Elsayed et al. 2014, Spier et al. 2015). The novel c.1270C>A (p.Leu424Ile) substitution at the same residue therefore meets PM5 at moderate strength. Details ▾Hide ▴
Evidence considered
- c.1270C>G (p.Leu424Val) is a well-established pathogenic variant at the same codon in germline PPAP
- p.Leu424Ile is a different missense change at the same residue.
Sources
PP3 Supportingp.L424I appears in Supplementary Table S2 of León-Castillo et al. 2020 with REVEL class 'likely disease causing' and only 1 benign in silico result (<=1), meeting the custom POLE PP3_Supporting rule. SpliceAI predicts no splicing impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- Table S2: L424I — SIFT=Deleterious
- PANTHER=Probably damaging
- SNAP2=effect
- PolyPhen2=Probably damaging
- PROVEAN=Neutral
- REVEL_class=likely disease causing
- number of benign=1. REVEL score=0.593. SpliceAI max delta=0.00.
Sources
Not met · 20 · evaluated, threshold not reached
PS2 No de novo occurrence of NM_006231.4:c.1270C>A has been reported in the reviewed literature. Published de novo reports at codon 424 all refer to the sister variant c.1270C>G (p.Leu424Val), not c.1270C>A. Details ▾Hide ▴
Evidence considered
- De novo reports exist for c.1270C>G (p.Leu424Val) but not for c.1270C>A (p.Leu424Ile).
Still missing
- No de novo observation for this exact variant.
Sources
PS3 No variant-specific functional data exist for NM_006231.4:c.1270C>A (p.Leu424Ile) in the reviewed literature. No systematic range characterization (tiling screen, saturation mutagenesis, systematic truncation series) covering position 424 that includes this exact substitution was identified. The OncoKB 'Likely Oncogenic' annotation reflects somatic curation context and does not constitute germline PS3 functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB curated annotation of Likely Oncogenic / Loss-of-function for the somatic context
- no germline functional data for the exact variant found in any reviewed publication.
Still missing
- No experimental functional data for p.Leu424Ile in any system
- no systematic range characterization covering this variant in a functional study.
Sources
PS4 The custom POLE PS4 rule requires recurrence in both COSMIC and TCGA with combined EC count >=10 and membership in the established pathogenic hotspot set. p.L424I has 0 COSMIC cases and 2 TCGA cases (total 2), does not meet the >=10 threshold, and is not one of the five established hotspot mutations (P286R, V411L, S297F, A456P, S459F). No germline case-control evidence exists for this variant. Details ▾Hide ▴
Evidence considered
- Supplementary Table S1: p.L424I (c.1270C>A) has 0 COSMIC
- 2 TCGA
- total 2 EC cases — below the custom framework threshold of >=10 combined cases and not in both COSMIC and TCGA.
Still missing
- No germline case-control data
- insufficient somatic recurrence to meet custom PS4 threshold.
Sources
vcep_path_250_323_s002vcep_path_250_323
PM6 No de novo observation has been reported for NM_006231.4:c.1270C>A specifically. De novo reports at codon 424 are for c.1270C>G (p.Leu424Val) only. Details ▾Hide ▴
Evidence considered
- De novo events reported for c.1270C>G (p.Leu424Val) but not for c.1270C>A (p.Leu424Ile).
Still missing
- No de novo observation for this exact variant.
Sources
PP1 No segregation data are available for NM_006231.4:c.1270C>A in any reviewed publication. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family studies or segregation analysis for this variant.
PP2 Insufficient data to determine whether POLE has a low rate of benign missense variation; no gene-level missense constraint metric (e.g., gnomAD Z-score, HCI prior) was available for this assessment. Details ▾Hide ▴
Evidence considered
- HCI prior not found
- no missense constraint metric available to assess PP2.
Still missing
- Missing gene-level missense constraint data.
PP4 No specific phenotypic data are available for any individual carrying NM_006231.4:c.1270C>A. The variant's phenotype cannot be assessed from the available evidence. Details ▾Hide ▴
Evidence considered
- No phenotype data specific to this variant.
Still missing
- No clinical phenotype available for variant carriers.
PP5 No reputable source has classified NM_006231.4:c.1270C>A as pathogenic. The single ClinVar submission classifies it as Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (Variation ID 1370405
- criteria provided
- single submitter).
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from all population databases.
Sources
BS1 The variant is absent from gnomAD. Allele frequency is 0%, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from all population databases.
Sources
BS2 No observation of this variant in healthy adult controls; the variant is absent from population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- no control observations to support BS2.
Sources
BS3 No functional studies demonstrating no deleterious effect for NM_006231.4:c.1270C>A (p.Leu424Ile) exist in the reviewed literature. Details ▾Hide ▴
Evidence considered
- No functional data showing benign effect.
Still missing
- No functional studies for this exact variant.
BS4 No segregation data demonstrating lack of cosegregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies for this variant.
BP1 Missense variants in POLE, particularly in the exonuclease domain, are a well-established mechanism of disease (PPAP). BP1 is contraindicated because the gene's disease spectrum includes pathogenic missense variants. Details ▾Hide ▴
Evidence considered
- POLE missense variants are a known cause of PPAP
- BP1 does not apply.
Sources
BP2 No observation of this variant in trans with a pathogenic POLE variant has been reported. Details ▾Hide ▴
Evidence considered
- No trans observations available.
Still missing
- No data on phase with other POLE variants.
BP4 The custom POLE BP4_Supporting rule requires REVEL class 'Likely benign' and >=4 benign in silico results. p.L424I has REVEL class 'likely disease causing' and only 1 benign result in Table S2, so it does not meet the custom BP4 rule. Under generic ACMG, the in silico evidence is mixed (REVEL 0.593 is indeterminate; BayesDel -0.085 leans benign but is not strongly predictive; SpliceAI = 0.00), which does not reach the threshold for BP4_Supporting. Details ▾Hide ▴
Evidence considered
- Table S2: REVEL_class=likely disease causing (not Likely benign)
- number of benign=1 (not >=4). REVEL=0.593 (indeterminate)
- BayesDel=-0.085 (benign-leaning but weakly predictive)
- SpliceAI=0.00.
Sources
BP5 No alternative molecular cause for the observed phenotype has been identified in any individual carrying this variant. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses.
Still missing
- No alternative cause identified.
BP6 ClinVar classification is 'Uncertain significance' (single submitter), not 'Benign' or 'Likely benign' from a reputable source. Details ▾Hide ▴
BP7 NM_006231.4:c.1270C>A is a missense variant, not a synonymous variant. BP7 applies only to synonymous variants predicted to have no splicing impact. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- BP7 is specific to synonymous variants.
PS5 No reputable source has classified NM_006231.4:c.1270C>A as pathogenic. ClinVar classification is Uncertain significance (single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (Variation ID 1370405
- criteria provided
- single submitter).
Still missing
- No established pathogenic classification from any source.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.1270C>A is a missense variant (p.Leu424Ile) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- PVS1 decision tree does not apply to non-null variants per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_gene_context
PS1 N/ANo previously established pathogenic variant produces the same amino acid change (p.Leu424Ile) via a different nucleotide substitution. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change resulting in p.Leu424Ile is known.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.1270C>A
- Protein (HGVS p.)
- NP_006222.2:p.(Leu424Ile)
- GRCh38
- chr12:132673664 G>T
- GRCh37
- chr12:133250250 G>T
- ClinVar
- 1370405
- COSMIC
- COSV57691098
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.593
- BayesDel
- -0.085
How the predictions were used
PP3 Supportingp.L424I appears in Supplementary Table S2 of León-Castillo et al. 2020 with REVEL class 'likely disease causing' and only 1 benign in silico result (<=1), meeting the custom POLE PP3_Supporting rule. SpliceAI predicts no splicing impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- Table S2: L424I — SIFT=Deleterious
- PANTHER=Probably damaging
- SNAP2=effect
- PolyPhen2=Probably damaging
- PROVEAN=Neutral
- REVEL_class=likely disease causing
- number of benign=1. REVEL score=0.593. SpliceAI max delta=0.00.
Sources
BP4 The custom POLE BP4_Supporting rule requires REVEL class 'Likely benign' and >=4 benign in silico results. p.L424I has REVEL class 'likely disease causing' and only 1 benign result in Table S2, so it does not meet the custom BP4 rule. Under generic ACMG, the in silico evidence is mixed (REVEL 0.593 is indeterminate; BayesDel -0.085 leans benign but is not strongly predictive; SpliceAI = 0.00), which does not reach the threshold for BP4_Supporting. Details ▾Hide ▴
Evidence considered
- Table S2: REVEL_class=likely disease causing (not Likely benign)
- number of benign=1 (not >=4). REVEL=0.593 (indeterminate)
- BayesDel=-0.085 (benign-leaning but weakly predictive)
- SpliceAI=0.00.
Sources
BP7 NM_006231.4:c.1270C>A is a missense variant, not a synonymous variant. BP7 applies only to synonymous variants predicted to have no splicing impact. Details ▾Hide ▴
Evidence considered
- This is a missense variant
- BP7 is specific to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.593. BayesDel score = -0.0845628.
9 paper records listed. 5 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 23263490 ↗Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Palles C et al. · 2013 FebIdentifies POLE c.1270C>G (p.Leu424Val) and POLD1 c.1433G>A (p.Ser478Asn) as high-penetrance germline mutations causing polymerase proofreading-associated polyposis (PPAP). The study established Leu424Val as a recurrent pathogenic variant in 13 families. NM_006231.4:c.1270C>A (p.Leu424Ile) was not observed or reported.→ PM5 Does not name this variant
Source detail
POLE L424V (NM_006231:c.C1270G)
Location Results; the only variant at codon 424 is c.1270C>G (p.Leu424Val).
-
PMID 24501277 ↗New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.Valle L et al. · 2014 Jul 1Screens 858 familial/early-onset CRC and polyposis patients for POLE c.1270C>G (p.Leu424Val) and POLD1 c.1433G>A (p.Ser478Asn). Identifies one de novo POLE p.L424V case. c.1270C>A was not assessed or detected.→ PM5 Does not name this variant
Source detail
All reported cases carried POLE c.1270C>G (p.Leu424Val)
Location Abstract and Results; the only codon 424 variant discussed is c.1270C>G (p.Leu424Val).
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PMID 25370038 ↗Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.Elsayed FA et al. · 2015 AugScreens 1188 Dutch familial CRC and polyposis patients for POLE c.1270C>G (p.Leu424Val). Three carriers identified, including one de novo case. c.1270C>A was not assessed or detected.→ PM5 Does not name this variant
Source detail
previously described heterozygous germline variants POLE c.1270C>G, p.(Leu424Val)
Location Abstract and Results; only c.1270C>G (p.Leu424Val) was genotyped.
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PMID 25529843 ↗Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.Spier I et al. · 2015 Jul 15Comprehensively characterizes the frequency and phenotypic spectrum of POLE and seven other polymerase gene mutations in 266 patients with colorectal adenomas and carcinomas. POLE c.1270C>G (p.Leu424Val) was detected in 3 unrelated families and is discussed in detail. c.1270C>A was not identified.→ PM5 Does not name this variant
Source detail
The POLE mutation c.1270C>G;p.Leu424Val was detected in three unrelated families
Location Results; the only codon 424 variant discussed is c.1270C>G (p.Leu424Val).
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PMID 27683556 ↗Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy.Johanns TM et al. · 2016 NovReports a case of glioblastoma with hypermutated genotype in a patient with germline POLE deficiency due to the L424V (c.1270C>G) substitution. Describes immunogenomic profiling and response to pembrolizumab. c.1270C>A was not identified.→ PM5 Does not name this variant
Source detail
tested positive for a POLE mutation encoding the L424V substitution, previously implicated in colorectal cancer susceptibility
Location Results; the germline POLE mutation is L424V (c.1270C>G).
Other recorded publications
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PMID 25228659 ↗Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.Characterizes the mutational signatures of tumors with somatic POLE exonuclease domain mutations (POLE-exo*) across multiple cancer types. The study classifies POLE-exo* tumors into groups A and B based on mutation patterns but does not specifically identify or test NM_006231.4:c.1270C>A (p.Leu424Ile).Does not name this variant
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PMID 12424237 ↗Okazaki fragment maturation in yeast. II. Cooperation between the polymerase and 3'-5'-exonuclease activities of Pol delta in the creation of a ligatable nick.Jin YH et al. · 2003Studies Okazaki fragment maturation in yeast using exonuclease-deficient Pol delta (POLD1) mutants. Focuses on Saccharomyces cerevisiae Pol3 alleles (pol3-01, pol3-5DV) and does not address human POLE or the c.1270C>A variant.Does not name this variant
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PMID 16699561 ↗A method to select for mutator DNA polymerase deltas in Saccharomyces cerevisiae.Murphy K et al. · 2006Describes a genetic method to select for mutator DNA polymerase delta variants in yeast. Discusses conserved exonuclease domain motifs in proofreading DNA polymerases but does not test or reference human POLE c.1270C>A.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. · 2017Describes the Sherloc comprehensive refinement of ACMG-AMP variant classification criteria. A methodology/review paper that does not discuss or test any specific POLE variant, including c.1270C>A.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 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/1370405/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133250250-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132673664-G-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132673664-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.1270…
- OncoKB ↗www.oncokb.org/gene/POLE/L424I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126826463
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1370405)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.593. BayesDel score = -0.0845628.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57691098, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.