About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.1871A>C, p.(His624Pro)
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
NM_006231.4:c.1871A>C (p.His624Pro) is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), comprising a total population of over 300,000 alleles without observation. This supports a pathogenic role for a rare missense variant in a gene where pathogenic variants are established.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Only one supporting-level pathogenic criterion (PM2_Supporting) is met. The León-Castillo 2020 custom POLE framework adopts generic ACMG/AMP 2015 final combination rules, under which a single supporting criterion is insufficient to reach Likely Pathogenic (minimum: PVS1 + 2 Supporting, 1 Strong + 2 Supporting, 3 Moderate, 2 Moderate + 2 Supporting, or 1 Moderate + 4 Supporting), nor does any benign-classification combination apply. The variant defaults to 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
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
0.010 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
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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.
29 criteria with recorded statuses: 1 met · 23 not met · 0 not assessed · 5 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.1871A>C (p.His624Pro) is a missense variant in exon 19 of POLE, located in the C-terminal polymerase domain outside the exonuclease domain (residues ~268–471) where established pathogenic hotspot variants cluster.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, comprising over 300,000 population alleles without observation (PM2_Supporting).
The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV001206773), and no additional submissions from expert panels are available.
The León-Castillo et al. 2020 custom POLE framework does not assign PM1, PS4, PP3, or BP4 to this variant, as p.His624Pro is absent from all supplementary tables (S1, S2, S3) and is not among the established exonuclease-domain hotspot or recurrent variants.
Computational analyses are equivocal: REVEL score 0.712 is borderline; BayesDel score 0.151 is modest; SpliceAI predicts no splicing impact (max delta 0.01). These do not meet thresholds for PP3 or BP4 under either the custom or generic frameworks.
No variant-specific functional studies, segregation data, de novo observations, case-control enrichment, or phenotype specificity data were identified in the literature or public databases.
With only PM2_Supporting met, this variant does not reach the threshold for Likely Pathogenic (requires ≥2 Supporting with at least PVS1, or 1 Moderate + 4 Supporting, etc.) or Likely Benign (requires ≥2 Supporting benign). The variant remains classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingNM_006231.4:c.1871A>C (p.His624Pro) is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), comprising a total population of over 300,000 alleles without observation. This supports a pathogenic role for a rare missense variant in a gene where pathogenic variants are established. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 624 resulting in the same amino acid substitution (p.His624Pro) that has been previously classified as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar lists only NM_006231.4:c.1871A>C at this codon
- classified as VUS.
PS2 No de novo occurrence data available for this variant. PS2 requires a confirmed de novo observation with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo testing or trio data available.
PS3 No variant-specific functional evidence was identified. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications were found reporting functional characterization of NM_006231.4:c.1871A>C (p.His624Pro). Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific reviewed functional evidence.
Still missing
- No functional assays performed on this variant.
Sources
PS4 The POLE custom framework (León-Castillo 2020) restricts PS4_Supporting to exact established pathogenic hotspot variants (P286R, V411L, A456P, S297F) that are recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined EC count ≥10. p.His624Pro is not among these variants and is absent from Supplementary Table S1. No germline case-control data are available. PS4 is not met. Details ▾Hide ▴
Evidence considered
- p.His624Pro is absent from Supplementary Table S1 (recurrent POLE variants in COSMIC/TCGA EC cohorts).
- Variant is not among the León-Castillo established pathogenic hotspot set.
- No germline case-control data available.
Sources
vcep_path_250_323_s002vcep_path_250_323
PM1 p.His624Pro is located at residue 624 in the C-terminal polymerase domain of POLE, outside the exonuclease domain (residues ~268–471) where established pathogenic hotspot variants cluster. The León-Castillo 2020 custom framework limits PM1 to exact exonuclease-domain hotspot variants listed in the paper and Supplementary Table S1; p.His624Pro is not among them. No evidence of a statistically significant mutational hotspot at this residue. Details ▾Hide ▴
Evidence considered
- Residue 624 is outside the POLE exonuclease domain (residues ~268–471).
- p.His624Pro is not listed in León-Castillo Supplementary Table S1 (recurrent variants).
- No statistically significant hotspot at this residue.
Sources
vcep_path_250_323_s002vcep_path_250_323vcep_path_250_323_s003vcep_path_250_323_s004
PM5 No same-residue (codon 624) comparator missense variant with a different amino acid change has been identified as pathogenic or likely pathogenic. Automated PM5 candidate harvesting could not confirm classic same-residue semantics. PM5 cannot be applied. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: found=false
- no same-residue pathogenic comparator variants.
PM6 No de novo observation has been reported for this variant. PM6 requires a confirmed de novo event with both maternity and paternity confirmed, or a confirmed de novo with an unconfirmed parental relationship at a lower strength. Details ▾Hide ▴
Still missing
- No de novo testing or trio data available.
PP1 No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family studies or segregation data available.
PP2 No HCI prior probability score is available for POLE. PP2 requires a demonstrated low rate of benign missense variation in the gene and evidence that missense variants are a common disease mechanism. While POLE exonuclease-domain missense variants are an established pathogenic mechanism, the HCI metric cannot be evaluated for this specific variant, and the variant lies outside the exonuclease domain where pathogenic missense variants are concentrated. Details ▾Hide ▴
Evidence considered
- HCI prior not found for POLE.
- Variant lies outside the exonuclease domain (residue 624 vs. domain at ~268–471).
Still missing
- HCI prior score not available for POLE.
PP3 p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom PP3 rule does not apply. Under generic in silico assessment: REVEL score 0.712 is borderline and does not clearly exceed established pathogenic thresholds; BayesDel score 0.151 is modest; SpliceAI max delta score 0.01 predicts no splicing impact. Multiple lines of computational evidence do not convincingly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.712 (borderline
- not strongly pathogenic).
- BayesDel: 0.150613 (modest).
- SpliceAI: max delta 0.01 (neutral
- no predicted splicing impact).
- Variant is absent from León-Castillo Supplementary Tables S2 and S3.
Sources
PP4 No information is available regarding the clinical phenotype or specificity of presentation for this variant. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Still missing
- No phenotype data available for variant carriers.
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (single submitter
- Labcorp Genetics
- SCV001206773).
Sources
BA1 NM_006231.4:c.1871A>C is absent from all gnomAD population databases (v2.1, v4.1, Canada). The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BS1 NM_006231.4:c.1871A>C is absent from all gnomAD population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BS2 No data are available regarding observation of this variant in healthy adult individuals in a context that would support a benign classification. BS2 requires observation in trans with a pathogenic variant or in a healthy adult for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No healthy control genotype data available for this variant.
BS3 No functional evidence demonstrating a neutral or benign effect has been identified for this variant. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional data. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No functional assays performed on this variant.
Sources
BS4 No segregation data are available for this variant. BS4 requires lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family studies or segregation data available.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. POLE has well-established pathogenic missense variants in the exonuclease domain (P286R, V411L, S297F, A456P, S459F), indicating that missense changes are a recognized disease mechanism for this gene. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- POLE has known pathogenic exonuclease-domain missense variants (P286R
- V411L
- S297F
- A456P
- S459F).
- Missense variants are an established disease mechanism in POLE.
Sources
vcep_path_250_323
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant in POLE. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Still missing
- No phase-resolved genotype data available.
BP4 p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom BP4 rule does not apply. Under generic in silico assessment: SpliceAI predicts no splicing impact (max delta 0.01); REVEL score 0.712 is borderline; BayesDel score 0.151 does not indicate a benign profile. Multiple lines of computational evidence do not clearly suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (neutral).
- REVEL: 0.712 (borderline
- not clearly benign).
- BayesDel: 0.150613 (not clearly benign).
- Variant is absent from León-Castillo Supplementary Tables S2 and S3.
Sources
BP5 No evidence of an alternate molecular basis for disease has been identified in individuals carrying this variant. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data available.
BP6 No reputable source has reported this variant as benign or likely benign. ClinVar classification is Uncertain significance (single submitter). Details ▾Hide ▴
PS5 No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain significance (single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided single submitter (Labcorp Genetics).
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006231.4:c.1871A>C is a missense variant (p.His624Pro). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant.
- pvs1_variant_assessment confirms apply_generic_pvs1_framework: false.
Sources
PM3 N/APM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. POLE-associated disease is not established as recessive, and no recessive inheritance context is available for this variant. Details ▾Hide ▴
Evidence considered
- No recessive inheritance context for POLE.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_006231.4:c.1871A>C is a missense substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel or stop-loss.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_006231.4:c.1871A>C is a missense substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006231.4:c.1871A>C is a missense substitution (p.His624Pro), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.1871A>C
- Protein (HGVS p.)
- NP_006222.2:p.(His624Pro)
- GRCh38
- chr12:132668863 T>G
- GRCh37
- chr12:133245449 T>G
- ClinVar
- 840940
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
- 0.712
- BayesDel
- 0.151
How the predictions were used
PP3 p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom PP3 rule does not apply. Under generic in silico assessment: REVEL score 0.712 is borderline and does not clearly exceed established pathogenic thresholds; BayesDel score 0.151 is modest; SpliceAI max delta score 0.01 predicts no splicing impact. Multiple lines of computational evidence do not convincingly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.712 (borderline
- not strongly pathogenic).
- BayesDel: 0.150613 (modest).
- SpliceAI: max delta 0.01 (neutral
- no predicted splicing impact).
- Variant is absent from León-Castillo Supplementary Tables S2 and S3.
Sources
BP4 p.His624Pro is not present in the León-Castillo supplementary in silico tables (S2 or S3), so the custom BP4 rule does not apply. Under generic in silico assessment: SpliceAI predicts no splicing impact (max delta 0.01); REVEL score 0.712 is borderline; BayesDel score 0.151 does not indicate a benign profile. Multiple lines of computational evidence do not clearly suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (neutral).
- REVEL: 0.712 (borderline
- not clearly benign).
- BayesDel: 0.150613 (not clearly benign).
- Variant is absent from León-Castillo Supplementary Tables S2 and S3.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006231.4:c.1871A>C is a missense substitution (p.His624Pro), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.712. BayesDel score = 0.150613.
1 paper record 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 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc framework, a refinement of the ACMG-AMP variant classification criteria. NM_006231.4:c.1871A>C (p.His624Pro) is not mentioned in this paper.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 0.010
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/840940/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133245449-T-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132668863-T-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132668863-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.1871…
- OncoKB ↗www.oncokb.org/gene/POLE/H624P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.1871A%3EC
- 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 = 840940)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.712. BayesDel score = 0.150613.
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.