0%
POLEc.4006-15C>TUncertain significance
Print report
Variant interpretation report

POLE c.4006-15C>T, p.?

NM_006231.4:c.4006-15C>T NP_006222.2:p.? View identifiers
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.

About POLE

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Met
PM2

The variant is rare in population databases: gnomAD v2.1 total AF is 2.04127e-05 (0.00204%) with grpmax FAF 2.326e-05, and gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) with grpmax FAF 3.005e-05; these values are below the generic PM2 rarity threshold of 0.1%.

Benign criteria applied · 1
BP4Met
BP4

Computational evidence supports no impact on splicing because the SpliceAI maximum delta score is 0.03, which is below the splice-impact threshold of 0.2.

Recorded classification: Uncertain significance

Conflicting supporting evidence under generic ACMG/AMP: PM2 is met for rarity and BP4 is met for benign computational splicing 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
21 / 1,456,334 alleles

gnomAD v4.1: 21 / 1,456,334 alleles. Recorded AF 1.44198e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.04127e-05; MAF= 0.00204%, 5/244946 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.77552e-05; MAF= 0.00878%, 3/34186 alleles, homozygotes = 0); grpmax FAF= 2.326e-05.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
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 · 4 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.

gnomAD v4.1 likewise shows a total AF of 1.44198e-05 (0.00144%) and grpmax FAF 3.005e-05, which remains below the generic PM2 rarity threshold of 0.1% and confirms that the variant is uncommon in the general population.

SpliceAI predicts minimal splicing effect, with a maximum delta score of 0.03, which is below the splice-impact threshold of 0.2 and supports BP4.

ClinVar contains a likely benign classification for this variant with single-submitter review status, which is concordant with a benign leaning but is not used as stand-alone classification evidence.

Because the available data provide one supporting pathogenic criterion for rarity and one supporting benign criterion for computational evidence against splice disruption, NM_006231.4:c.4006-15C>T is classified as a variant of uncertain significance.

Met · 2

PM2 MetThe variant is rare in population databases: gnomAD v2.1 total AF is 2.04127e-05 (0.00204%) with grpmax FAF 2.326e-05, and gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) with grpmax FAF 3.005e-05; these values are below the generic PM2 rarity threshold of 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 2.04127e-05; grpmax FAF 2.326e-05
  • gnomAD v4.1 AF 1.44198e-05; grpmax FAF 3.005e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 MetComputational evidence supports no impact on splicing because the SpliceAI maximum delta score is 0.03, which is below the splice-impact threshold of 0.2. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.01, DS_AL 0.03, DS_DG 0.01, DS_DL 0.00; max delta 0.03
Sources
spliceai ↗

Not met · 4 · evaluated, threshold not reached

PVS1 NM_006231.4:c.4006-15C>T is an intronic variant 15 bases upstream of exon 32, and SpliceAI shows a maximum delta score of 0.03, which is below the splicing concern threshold of 0.2; no evidence in the case file demonstrates a null effect or predicted exon skipping/cryptic splice creation sufficient for PVS1. Details ▾Hide ▴
Evidence considered
  • Intronic location c.4006-15
  • SpliceAI max delta score 0.03
Sources
spliceai ↗
PP3 Computational evidence does not support a deleterious splicing effect because the SpliceAI maximum delta score is 0.03, which is below the commonly used splice-impact threshold of 0.2. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.03
Sources
spliceai ↗
BA1 Benign stand-alone frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both well below the generic BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 2.04127e-05
  • gnomAD v4.1 AF 1.44198e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Benign strong frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both below the generic BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 2.04127e-05
  • gnomAD v4.1 AF 1.44198e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS1 PS1 requires the same amino acid change as an established pathogenic variant, and no such matched protein-altering comparison is relevant for this intronic variant in the available record. Details ▾Hide ▴

No further detail was recorded.

PS2 No de novo data with confirmed maternity and paternity are provided. Details ▾Hide ▴
Still missing
  • De novo testing data are not available.
PS3 No functional assay demonstrating a damaging effect on POLE splicing or function is provided. Details ▾Hide ▴
Still missing
  • Variant-specific functional data are not available.
PS4 No case-control enrichment, case series, or prevalence comparison supporting increased occurrence in affected individuals is provided. Details ▾Hide ▴
Still missing
  • Case enrichment data are not available.
Sources
PMID:28492532 ↗
PM1 No evidence places this intronic position in a defined mutational hot spot or critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • OncoKB gene page retrieval failed; no variant-specific hotspot evidence available
Still missing
  • Hotspot/domain evidence is not available for this intronic site.
Sources
oncokb ↗
PM6 No assumed de novo occurrence data are provided. Details ▾Hide ▴
Still missing
  • De novo occurrence data are not available.
PP1 No segregation data are provided. Details ▾Hide ▴
Still missing
  • Family segregation data are not available.
PP4 No phenotype, tumor spectrum, or family history data specific enough to POLE-associated disease are provided. Details ▾Hide ▴
Still missing
  • Phenotype-specific evidence is not available.
PP5 Although ClinVar contains a classification, PP5 is not applied here as stand-alone evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign; review status: criteria provided, single submitter
Sources
clinvar ↗PMID:28492532 ↗
BS2 No data demonstrate observation in healthy adult individuals at a level sufficient for BS2. Details ▾Hide ▴
Evidence considered
  • No homozygotes reported in gnomAD v2.1 or v4.1
Still missing
  • Well-phenotyped unaffected carrier data are not available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional assay demonstrating a benign effect is provided. Details ▾Hide ▴
Still missing
  • Variant-specific benign functional data are not available.
BS4 No nonsegregation data are provided. Details ▾Hide ▴
Still missing
  • Family segregation data are not available.
BP2 No phase data with another pathogenic variant are provided. Details ▾Hide ▴
Still missing
  • Phase information is not available.
BP5 No alternate molecular explanation or case-level data are provided to support BP5. Details ▾Hide ▴
Still missing
  • Case-specific alternate etiology data are not available.
BP6 ClinVar lists this variant as likely benign with single-submitter review status, but BP6 is not used here as stand-alone evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign; 2 clinical laboratories; review status: criteria provided, single submitter
Sources
clinvar ↗
BP7 The intronic position and low SpliceAI score are compatible with a benign splicing interpretation, but the available record does not provide the additional conservation assessment needed to apply BP7 confidently. Details ▾Hide ▴
Evidence considered
  • Intronic position c.4006-15
  • SpliceAI max delta score 0.03
Still missing
  • Conservation assessment for the affected intronic nucleotide is not available.
Sources
spliceai ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is a recessive-phase criterion, and no recessive POLE context is established for this case. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes, which are not relevant to this intronic noncoding variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense changes at the same residue and is not relevant to this intronic variant. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 is a missense-specific criterion and is not relevant to this intronic variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 is a missense-specific criterion and is not relevant to this intronic variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions and is not relevant to this intronic SNV. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.4006-15C>T
Protein (HGVS p.)
NP_006222.2:p.?
GRCh38
chr12:132649087 G>A
GRCh37
chr12:133225673 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…
gnomAD v4.1 21 / 1,456,334 alleles AF 1.44e-05 · 0 homozygotes · FAF 3.01e-05
gnomAD v2.1 5 / 244,946 alleles AF 2.04e-05 · 0 homozygotes · FAF 2.33e-05

By genetic ancestry

gnomAD v4.1

AF 1.4e-05 · 21 / 1,456,334 alleles · 0 hom · FAF 3e-05
South Asian6 / 85,896 7e-05
Admixed American3 / 44,452 6.7e-05
Remaining individuals2 / 60,188 3.3e-05
African/African American1 / 33,410 3e-05
European (non-Finnish)9 / 1,110,426 8.1e-06
0 alternate alleles recorded in 4 other groups: European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian.

gnomAD v2.1

AF 2e-05 · 5 / 244,946 alleles · 0 hom · FAF 2.3e-05
Admixed American3 / 34,186 8.8e-05
South Asian2 / 30,214 6.6e-05
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.44198e-05; MAF= 0.00144%, 21/1456334 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.98519e-05; MAF= 0.00699%, 6/85896 alleles, homozygotes = 0); grpmax FAF= 3.005e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.04127e-05; MAF= 0.00204%, 5/244946 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.77552e-05; MAF= 0.00878%, 3/34186 alleles, homozygotes = 0); grpmax FAF= 2.326e-05.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 MetComputational evidence supports no impact on splicing because the SpliceAI maximum delta score is 0.03, which is below the splice-impact threshold of 0.2. Details ▾Hide ▴
Evidence considered
  • SpliceAI DS_AG 0.01, DS_AL 0.03, DS_DG 0.01, DS_DL 0.00; max delta 0.03
Sources
spliceai ↗
PP3 Computational evidence does not support a deleterious splicing effect because the SpliceAI maximum delta score is 0.03, which is below the commonly used splice-impact threshold of 0.2. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.03
Sources
spliceai ↗
BP7 The intronic position and low SpliceAI score are compatible with a benign splicing interpretation, but the available record does not provide the additional conservation assessment needed to apply BP7 confidently. Details ▾Hide ▴
Evidence considered
  • Intronic position c.4006-15
  • SpliceAI max delta score 0.03
Still missing
  • Conservation assessment for the affected intronic nucleotide is not available.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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 21 / 1,456,334 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

All source links

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= 1.44198e-05; MAF= 0.00144%, 21/1456334 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.98519e-05; MAF= 0.00699%, 6/85896 alleles, homozygotes = 0); grpmax FAF= 3.005e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.04127e-05; MAF= 0.00204%, 5/244946 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.77552e-05; MAF= 0.00878%, 3/34186 alleles, homozygotes = 0); grpmax FAF= 2.326e-05.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).