About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.6111C>T, p.(Ala2037=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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 Not recorded. 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP6Supporting
BP6 · supporting
ClinVar contains benign/likely benign clinical laboratory classifications for this variant (Likely benign from 4 laboratories and Benign from 1 laboratory), supporting BP6 at a supporting level under the generic ACMG/AMP framework.
BP7Supporting
BP7 · supporting
This is a synonymous variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.
Recorded classification: Likely benign
Generic ACMG/AMP 2015 fallback using the retrieved generic_acmg_combination_rules; two supporting benign criteria were applied (BP6 and BP7), which matches the generic ACMG/AMP Likely Benign combination rule.
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
67 / 1,613,852 alleles
gnomAD v4.1: 67 / 1,613,852 alleles. Recorded AF 4.15156e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.97368e-05; MAF= 0.00497%, 14/281482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228698; MAF= 0.02287%, 7/30608 alleles, homozygotes = 0); grpmax FAF= 0.00010658.
No listed criterion applied
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.
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.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 8 not assessed · 11 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.6111C>T is a synonymous POLE variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.
The variant has been submitted to ClinVar as Likely benign by 4 clinical laboratories and as Benign by 1 clinical laboratory, supporting BP6 under the generic ACMG/AMP framework.
Population frequency is low in gnomAD v4.1 at 4.15156e-05 (0.00415%), which is below the BS1 threshold of 0.3% and the BA1 threshold of 1.0%, so benign frequency criteria stronger than supporting are not met.
Using the retrieved generic ACMG/AMP final classification combination rules, BP6 plus BP7 constitutes two supporting benign criteria and is consistent with a Likely benign classification.
No criteria match.
Met · 2
BP6 SupportingClinVar contains benign/likely benign clinical laboratory classifications for this variant (Likely benign from 4 laboratories and Benign from 1 laboratory), supporting BP6 at a supporting level under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- ClinVar variation 391387: Likely benign from 4 clinical laboratories and Benign from 1 clinical laboratory; review status 'criteria provided, single submitter'.
Sources
BP7 SupportingThis is a synonymous variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7. Details ▾Hide ▴
Evidence considered
- Protein consequence NP_006222.2:p.(Ala2037=).
- SpliceAI max delta score 0.05 with evidence sentence 'no significant splice impact'.
Sources
Not met · 7 · evaluated, threshold not reached
PS3 No well-established functional study demonstrating a damaging effect for this specific variant was retrieved, and PS3 screening did not identify supporting publications. Details ▾Hide ▴
Evidence considered
- screen_PS3.json contained no passed studies for this variant.
Sources
PS4 No case-control enrichment or convincing excess of affected observations over controls was retrieved; COSMIC reported only a single somatic occurrence, which does not support germline PS4. Details ▾Hide ▴
Evidence considered
- COSMIC somatic count was 1 for COSV107342250.
- screen_PS4.json contained no passed studies for this variant.
Sources
PM1 The variant was not identified in a statistically significant hotspot, so location-based pathogenic enrichment was not demonstrated. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots found no hotspot row for POLE A2037.
- OncoKB did not show variant-specific oncogenic curation.
Sources
PM2 The variant is present in population databases, and no gene-specific rule was retrieved to treat rarity alone as pathogenic evidence for this synonymous change. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 4.973675048493332e-05 (14/281482).
- gnomAD v4.1 AF 4.151557887588205e-05 (67/1613852).
Sources
BA1 The gnomAD v4.1 total allele frequency is 4.15156e-05 (0.00415%), which is below the benign stand-alone threshold of 1.0%, so BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF 4.151557887588205e-05; 67/1613852 alleles; 0 homozygotes.
Sources
BS1 The highest observed population frequency is 9.88099e-05 in gnomAD v4.1 South Asians (0.00988%), which is below the benign strong threshold of 0.3%, so BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 South Asian AF 9.880988977207852e-05; 9/91084 alleles; 0 homozygotes.
Sources
BS3 No well-established functional study demonstrating no damaging effect for this specific variant was retrieved, and BS3 screening did not identify supporting publications. Details ▾Hide ▴
Evidence considered
- screen_BS3.json contained no passed studies for this variant.
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo data were retrieved. Details ▾Hide ▴
Still missing
- Parental testing and confirmed maternity/paternity data were not available.
PM6 No assumed de novo evidence was retrieved. Details ▾Hide ▴
Still missing
- Limited family testing information.
PP1 No segregation data were retrieved. Details ▾Hide ▴
Still missing
- Family segregation studies were not available.
PP4 No phenotype-specific evidence linking this variant to a highly specific POLE-associated clinical presentation was retrieved. Details ▾Hide ▴
Still missing
- Detailed phenotype and family history were not available.
BS2 No evidence was retrieved to support observation in healthy adult individuals at a level sufficient for BS2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 homozygotes = 0.
- gnomAD v4.1 homozygotes = 0.
Still missing
- Disease-specific penetrance and BS2 applicability were not established in the workspace.
Sources
BS4 No segregation data showing lack of cosegregation were retrieved. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
BP2 No phase or co-occurrence data were retrieved. Details ▾Hide ▴
Still missing
- Phase information and co-occurrence data were not available.
BP5 No alternate molecular explanation for the phenotype was retrieved. Details ▾Hide ▴
Still missing
- Case-level phenotype and alternate-cause evaluation were not available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant NP_006222.2:p.(Ala2037=) is not a predicted loss-of-function allele. Details ▾Hide ▴
PS1 N/APS1 is not applicable because this is a synonymous change and does not create an alternate amino-acid substitution matching a known pathogenic variant. Details ▾Hide ▴
PM3 N/APM3 is not applicable because no recessive trans observations were retrieved and POLE constitutional disease in this review context was not framed for PM3 use. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 is not applicable because the variant does not change protein length or alter the reading frame. Details ▾Hide ▴
PM5 N/APM5 applies to novel missense changes at a residue with a different pathogenic missense variant and is not applicable to a synonymous variant. Details ▾Hide ▴
PP2 N/APP2 is a missense-gene criterion and is not applicable to a synonymous variant. Details ▾Hide ▴
PP3 N/APP3 was not applied because the variant is synonymous and computational evidence was more appropriately considered under BP7 rather than as pathogenic support. Details ▾Hide ▴
Evidence considered
- SpliceAI predicted no significant splice impact with max delta score 0.05.
Sources
PP5 N/ANo reputable source classified this variant as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar submissions were benign/likely benign, not pathogenic.
Sources
BP1 N/ABP1 is a missense-specific criterion and is not applicable to a synonymous variant. Details ▾Hide ▴
BP3 N/ABP3 applies to in-frame indels in repetitive regions and is not applicable to a synonymous single-nucleotide substitution. Details ▾Hide ▴
BP4 N/ABP4 was not separately applied because the computational evidence for this synonymous variant was considered under BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI predicted no significant splice impact with max delta score 0.05.
Sources
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.4
- Coding (HGVS c.)
- NM_006231.4:c.6111C>T
- Protein (HGVS p.)
- NP_006222.2:p.(Ala2037=)
- GRCh38
- chr12:132632689 G>A
- GRCh37
- chr12:133209275 G>A
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
67 / 1,613,852 alleles
AF 4.15e-05 · 0 homozygotes · FAF 6.81e-05
gnomAD v2.1
14 / 281,482 alleles
AF 4.97e-05 · 0 homozygotes · FAF 0.000107
By genetic ancestry
gnomAD v4.1
AF 4.2e-05 · 67 / 1,613,852 alleles · 0 hom · FAF 6.8e-05
| South Asian9 / 91,084 | 9.9e-05 |
| European (non-Finnish)56 / 1,179,988 | 4.7e-05 |
| Admixed American1 / 60,002 | 1.7e-05 |
| Remaining individuals1 / 62,482 | 1.6e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian, African/African American, Amish.
gnomAD v2.1
AF 5e-05 · 14 / 281,482 alleles · 0 hom · FAF 0.00011
| South Asian7 / 30,608 | 0.00023 |
| European (non-Finnish)6 / 128,300 | 4.7e-05 |
| Admixed American1 / 35,404 | 2.8e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.15156e-05; MAF= 0.00415%, 67/1613852 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.88099e-05; MAF= 0.00988%, 9/91084 alleles, homozygotes = 0); grpmax FAF= 6.806e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.97368e-05; MAF= 0.00497%, 14/281482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228698; MAF= 0.02287%, 7/30608 alleles, homozygotes = 0); grpmax FAF= 0.00010658.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7. Details ▾Hide ▴
Evidence considered
- Protein consequence NP_006222.2:p.(Ala2037=).
- SpliceAI max delta score 0.05 with evidence sentence 'no significant splice impact'.
Sources
PP3 N/APP3 was not applied because the variant is synonymous and computational evidence was more appropriately considered under BP7 rather than as pathogenic support. Details ▾Hide ▴
Evidence considered
- SpliceAI predicted no significant splice impact with max delta score 0.05.
Sources
BP4 N/ABP4 was not separately applied because the computational evidence for this synonymous variant was considered under BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI predicted no significant splice impact with max delta score 0.05.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
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
67 / 1,613,852 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
Cancer hotspots
Captured Cancer Hotspots source record
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/391387/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133209275-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132632689-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.4%3Ac.6111…
- OncoKB ↗www.oncokb.org/gene/POLE/A2037=
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= 4.15156e-05; MAF= 0.00415%, 67/1613852 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.88099e-05; MAF= 0.00988%, 9/91084 alleles, homozygotes = 0); grpmax FAF= 6.806e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.97368e-05; MAF= 0.00497%, 14/281482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228698; MAF= 0.02287%, 7/30608 alleles, homozygotes = 0); grpmax FAF= 0.00010658.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV107342250, n = 1 times).