About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.2172G>A, p.(Ala724=)
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
PM2Moderate
PM2 · moderate
Population frequency is below the project's PM2 threshold of 0.1% in both gnomAD v2.1 and gnomAD v4.1. The observed total allele frequency is 0.00400% in v2.1 (10/249782 alleles) and 0.00166% in v4.1 (26/1568268 alleles), which is below the 0.1% threshold.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
This is a synonymous variant, p.(Ala724=), with no amino-acid change. It is not a canonical splice consensus variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7.
Recorded classification: Uncertain significance
León-Castillo et al. 2020 custom POLE framework using ACMG/AMP 2015 final combination thresholds
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
26 / 1,568,268 alleles
gnomAD v4.1: 26 / 1,568,268 alleles. Recorded AF 1.65788e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.00349e-05; MAF= 0.00400%, 10/249782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000326878; MAF= 0.03269%, 8/24474 alleles, homozygotes = 0); grpmax FAF= 0.00015631.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The POLE c.2172G>A (p.Ala724=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign, with five likely benign submissions and one submission of uncertain significance.
This variant is present at low frequency in gnomAD, with total allele frequencies of 0.00400% in v2.1 and 0.00166% in v4.1, both below the project's PM2 threshold of 0.1% and below the BS1 threshold of 0.3%.
This is a synonymous change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01; it is also not among the missense hotspot or computationally selected variants used for the custom POLE PM1, PS4, PP3, and BP4 rules.
No criteria match.
Met · 2
PM2 ModeratePopulation frequency is below the project's PM2 threshold of 0.1% in both gnomAD v2.1 and gnomAD v4.1. The observed total allele frequency is 0.00400% in v2.1 (10/249782 alleles) and 0.00166% in v4.1 (26/1568268 alleles), which is below the 0.1% threshold. Details ▾Hide ▴
Rule
Project default PM2 threshold for non-VCEP calls: AF <0.1%.
Evidence considered
- gnomAD v2.1 total AF=4.00349e-05 (0.00400%).
- gnomAD v4.1 total AF=1.65788e-05 (0.00166%).
Sources
BP7 SupportingThis is a synonymous variant, p.(Ala724=), with no amino-acid change. It is not a canonical splice consensus variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7. Details ▾Hide ▴
Rule
Synonymous variant with no predicted splice impact.
Evidence considered
- Protein consequence is p.(Ala724=).
- pvs1_variant_assessment reports canonical_splice_consensus=false.
- SpliceAI max delta score=0.01.
Sources
spliceai ↗pvs1_variant_assessment
Not met · 5 · evaluated, threshold not reached
PS4 This variant has not been reported in COSMIC, and it is not one of the exact recurrent pathogenic missense variants eligible for the custom POLE PS4 rule. Available evidence does not show increased prevalence in affected individuals sufficient to support PS4. Details ▾Hide ▴
Rule
Custom POLE PS4_Supporting requires an exact recurrent missense variant present in both COSMIC and TCGA EC cohorts with combined count >=10.
Evidence considered
- COSMIC search returned no result.
- The León-Castillo custom POLE PS4 rule is restricted to a small set of recurrent missense hotspots
- and this synonymous variant is not among them.
Still missing
- No germline case-control enrichment data were identified.
Sources
vcep_p_a_t_h___2_5_0___3_2_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_2
PM1 This is a synonymous variant, p.(Ala724=), and it is not one of the exact POLE missense hotspot or recurrent exonuclease-domain variants specified in the custom POLE PM1 framework. Available evidence does not support PM1. Details ▾Hide ▴
Rule
Custom POLE PM1 applies only to exact listed missense variants; domain membership alone is insufficient.
Evidence considered
- Cancer Hotspots review did not identify a significant hotspot at A724.
- The custom POLE PM1 rule applies only to exact listed missense variants from the León-Castillo framework.
Sources
PP3 This synonymous variant is not eligible for the custom POLE PP3 rule, which is restricted to exact missense variants listed in the León-Castillo supplementary computational tables. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, so available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Custom POLE PP3 applies only to exact missense variants in Table S2 or S3 with a likely disease-causing REVEL class and <=1 benign in silico result.
Evidence considered
- Variant was not identified in the POLE supplementary computational tables searched for A724/c.2172G>A.
- SpliceAI max delta score=0.01.
Sources
BA1 Population frequency does not reach the BA1 threshold of 1%. The observed total allele frequency is 0.00400% in gnomAD v2.1 and 0.00166% in gnomAD v4.1, which is below 1%. Details ▾Hide ▴
Rule
Project default BA1 threshold for non-VCEP calls: AF >1%.
Evidence considered
- gnomAD v2.1 total AF=0.00400%.
- gnomAD v4.1 total AF=0.00166%.
Sources
BS1 Population frequency does not exceed the BS1 threshold of 0.3%. The highest observed population frequency is 0.03269% in gnomAD v2.1 African/African American and 0.02041% in gnomAD v4.1 African/African American, both below 0.3%. Details ▾Hide ▴
Rule
Project default BS1 threshold for non-VCEP calls: AF >0.3%.
Evidence considered
- gnomAD v2.1 highest population AF=0.03269% (African/African American).
- gnomAD v4.1 highest population AF=0.02041% (African/African American).
Sources
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo data with parental testing were identified, so PS2 could not be assessed. Details ▾Hide ▴
Still missing
- Parental testing and confirmed de novo status were not available.
PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 could not be assessed. Details ▾Hide ▴
Still missing
- No variant-specific functional assay evidence was identified.
PM3 No data on allelic phase with another pathogenic variant were identified, so PM3 could not be assessed. Details ▾Hide ▴
Still missing
- No phase data or second pathogenic variant data were identified.
PM6 No assumed de novo data without confirmed parentage were identified, so PM6 could not be assessed. Details ▾Hide ▴
Still missing
- No de novo case information was identified.
PP1 No segregation data were identified, so PP1 could not be assessed. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
PP4 No phenotype or family history data sufficiently specific for POLE-related disease were identified, so PP4 could not be assessed. Details ▾Hide ▴
Still missing
- Phenotype specificity and clinical context were not provided.
BS2 Although this variant is present in population databases, no disease-specific evidence was identified to show observation in unaffected individuals is sufficient to support BS2. Details ▾Hide ▴
Evidence considered
- Population database presence alone was not considered sufficient for BS2.
Still missing
- No disease-specific BS2 framework or unaffected carrier data were identified.
Sources
BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 could not be assessed. Details ▾Hide ▴
Still missing
- No variant-specific benign functional assay evidence was identified.
BS4 No evidence showing lack of segregation with disease in affected family members was identified, so BS4 could not be assessed. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
BP2 No phase data or observations with another variant were identified, so BP2 could not be assessed. Details ▾Hide ▴
Still missing
- No cis/trans phase data were identified.
BP5 No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed. Details ▾Hide ▴
Still missing
- Phenotype context and other molecular findings were not available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a synonymous change, p.(Ala724=), and does not fall in the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice-site variants. Available evidence does not support use of PVS1 for this variant. Details ▾Hide ▴
Rule
Generic PVS1 fallback applies only to eligible null-variant classes after gene-level LOF review.
Evidence considered
- POLE is eligible for generic PVS1 fallback at the gene level
- but this specific variant is outside the generic PVS1 variant classes.
- pvs1_variant_assessment states apply_generic_pvs1_framework=false and canonical_splice_consensus=false.
Sources
PS1 N/APS1 is intended for a different nucleotide change producing the same amino acid change as an established pathogenic variant. This variant is synonymous and no qualifying PS1 evidence was identified. Details ▾Hide ▴
Evidence considered
- ClinVar record reviewed
- no PS1-type amino-acid equivalence evidence identified.
Still missing
- No established pathogenic amino-acid match was identified for PS1 evaluation.
Sources
PM4 N/APM4 applies to protein length changes caused by in-frame insertions, deletions, or stop-loss variants. This variant is synonymous and does not alter protein length. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala724=).
PM5 N/APM5 applies to a novel missense change at an amino-acid residue where a different missense change is established as pathogenic. This variant is synonymous and does not create a missense substitution. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala724=).
PP2 N/APP2 is a missense-based criterion and is not applicable to this synonymous variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala724=).
PP5 N/APP5 was not applied because external assertions alone were not used as primary evidence for this interpretation. Details ▾Hide ▴
BP1 N/ABP1 is a missense-based criterion and is not applicable to this synonymous variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Ala724=).
BP3 N/ABP3 applies to in-frame indels in repetitive regions without known function. This variant is a synonymous substitution and BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AThe custom POLE BP4 rule is restricted to exact missense variants represented in the León-Castillo supplementary computational tables. This variant is synonymous, so BP4 was not applied. Details ▾Hide ▴
Rule
Custom POLE BP4 applies only to exact missense variants in Table S2 or S3 with likely benign REVEL class and >=4 benign in silico results.
Evidence considered
- Custom POLE BP4 framework is limited to listed missense variants.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
BP6 N/ABP6 was not applied because external classifications alone were not used as stand-alone benign evidence. Details ▾Hide ▴
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.2172G>A
- Protein (HGVS p.)
- NP_006222.2:p.(Ala724=)
- GRCh38
- chr12:132668357 C>T
- GRCh37
- chr12:133244943 C>T
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
26 / 1,568,268 alleles
AF 1.66e-05 · 0 homozygotes · FAF 0.000125
gnomAD v2.1
10 / 249,782 alleles
AF 4e-05 · 0 homozygotes · FAF 0.000156
By genetic ancestry
gnomAD v4.1
AF 1.7e-05 · 26 / 1,568,268 alleles · 0 hom · FAF 0.00013
| African/African American15 / 73,490 | 0.0002 |
| Remaining individuals6 / 60,434 | 9.9e-05 |
| South Asian2 / 84,082 | 2.4e-05 |
| East Asian1 / 44,028 | 2.3e-05 |
| Admixed American1 / 54,054 | 1.9e-05 |
| European (non-Finnish)1 / 1,155,980 | 8.7e-07 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 4e-05 · 10 / 249,782 alleles · 0 hom · FAF 0.00016
| African/African American8 / 24,474 | 0.00033 |
| South Asian1 / 23,484 | 4.3e-05 |
| Admixed American1 / 29,764 | 3.4e-05 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.65788e-05; MAF= 0.00166%, 26/1568268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000204109; MAF= 0.02041%, 15/73490 alleles, homozygotes = 0); grpmax FAF= 0.00012516.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.00349e-05; MAF= 0.00400%, 10/249782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000326878; MAF= 0.03269%, 8/24474 alleles, homozygotes = 0); grpmax FAF= 0.00015631.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous variant, p.(Ala724=), with no amino-acid change. It is not a canonical splice consensus variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7. Details ▾Hide ▴
Rule
Synonymous variant with no predicted splice impact.
Evidence considered
- Protein consequence is p.(Ala724=).
- pvs1_variant_assessment reports canonical_splice_consensus=false.
- SpliceAI max delta score=0.01.
Sources
spliceai ↗pvs1_variant_assessment
PP3 This synonymous variant is not eligible for the custom POLE PP3 rule, which is restricted to exact missense variants listed in the León-Castillo supplementary computational tables. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, so available computational evidence does not support PP3. Details ▾Hide ▴
Rule
Custom POLE PP3 applies only to exact missense variants in Table S2 or S3 with a likely disease-causing REVEL class and <=1 benign in silico result.
Evidence considered
- Variant was not identified in the POLE supplementary computational tables searched for A724/c.2172G>A.
- SpliceAI max delta score=0.01.
Sources
BP4 N/AThe custom POLE BP4 rule is restricted to exact missense variants represented in the León-Castillo supplementary computational tables. This variant is synonymous, so BP4 was not applied. Details ▾Hide ▴
Rule
Custom POLE BP4 applies only to exact missense variants in Table S2 or S3 with likely benign REVEL class and >=4 benign in silico results.
Evidence considered
- Custom POLE BP4 framework is limited to listed missense variants.
Sources
vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
26 / 1,568,268 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/405837/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133244943-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132668357-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.2172…
- OncoKB ↗www.oncokb.org/gene/POLE/A724=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.2172G%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= 1.65788e-05; MAF= 0.00166%, 26/1568268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000204109; MAF= 0.02041%, 15/73490 alleles, homozygotes = 0); grpmax FAF= 0.00012516.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.00349e-05; MAF= 0.00400%, 10/249782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000326878; MAF= 0.03269%, 8/24474 alleles, homozygotes = 0); grpmax FAF= 0.00015631.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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.