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POLEc.6748-18G>AUncertain significance
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Variant interpretation report

POLE c.6748-18G>A, p.?

NM_006231.4:c.6748-18G>A 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 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

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.2e-05 (8/249,726 alleles), gnomAD v4.1 AF=8.2e-06 (13/1,594,924 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Only one criterion is met (PM2 at supporting strength). Under generic ACMG/AMP 2015 combination rules, a single supporting criterion is insufficient to satisfy any pathogenic, likely pathogenic, benign, or likely benign combination. The variant defaults to Variant of Uncertain Significance (VUS). The Leon-Castillo et al. 2020 custom POLE framework applies only to missense variants in the exonuclease domain and explicitly directs fallback to generic ACMG/AMP for this intronic variant.

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
13 / 1,594,924 alleles

gnomAD v4.1: 13 / 1,594,924 alleles. Recorded AF 8.15086e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.20351e-05; MAF= 0.00320%, 8/249726 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000327225; MAF= 0.03272%, 2/6112 alleles, homozygotes = 0); grpmax FAF= 7.539e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely benign.

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
No matching record reported

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

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.

27 criteria with recorded statuses: 1 met · 4 not met · 12 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_006231.4:c.6748-18G>A is an intronic variant in POLE (intron 48) that is present at extremely low frequency in population databases (gnomAD v2.1: 8/249,726 alleles, AF=0.0032%; gnomAD v4.1: 13/1,594,924 alleles, AF=0.00082%), meeting PM2 at supporting strength.

SpliceAI predicts no splice impact (max delta score 0.0), and this variant does not involve canonical splice consensus sequences. No functional studies or computational tools support a deleterious effect.

This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Invitae, SCV002332903, VCV001540941). The cited publication (PMID:28492532) is a methodology paper describing the Sherloc classification framework and does not provide variant-specific evidence.

The custom León-Castillo et al. 2020 POLE framework (PM1, PS4, PP3, BP4) applies only to missense variants in the exonuclease domain; this intronic variant is outside the scope of the custom rules, which rely on specific variant-level evidence from the paper's supplementary tables where this variant is absent.

Overall, only one criterion is met (PM2_Supporting), which is insufficient to reach a classification under ACMG/AMP 2015 combination rules. The variant remains a Variant of Uncertain Significance (VUS) by default, though the available evidence leans benign (ClinVar Likely benign, SpliceAI no impact).

Met · 1

PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.2e-05 (8/249,726 alleles), gnomAD v4.1 AF=8.2e-06 (13/1,594,924 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF 3.2e-05 (8/249
  • 726 alleles
  • 0 homozygotes)
  • gnomAD v4.1: AF 8.2e-06 (13/1
  • 594
  • 924 alleles
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PP3 SpliceAI predicts no splice impact (max delta 0.0). REVEL and BayesDel scores are not available for this intronic variant. The variant is absent from León-Castillo supplementary Tables S2 and S3. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice alteration.
  • REVEL and BayesDel not available (intronic variant).
  • Variant absent from León-Castillo Tables S2/S3.
Sources
spliceai ↗
BA1 Highest population allele frequency is 0.0327% (gnomAD v2.1, OTH subpopulation), far below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 max subpopulation AF: 0.0327% (OTH)
  • gnomAD v2.1 global AF: 0.0032%
  • gnomAD v4.1 max subpopulation AF: 0.0166% (Middle Eastern)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Global allele frequency is 0.0032% (gnomAD v2.1, 8/249,726 alleles), below the 0.3% BS1 threshold. This variant is not sufficiently common to support a benign interpretation via BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 global AF: 0.0032%
  • gnomAD v4.1 global AF: 0.00082%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SpliceAI predicts no splice impact (max delta 0.0), but multiple lines of computational evidence are not available for this intronic variant. REVEL and BayesDel are not applicable. The variant is absent from León-Castillo Tables S2/S3. Insufficient computational evidence to meet BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice alteration.
  • REVEL and BayesDel not available (intronic).
  • Variant absent from León-Castillo Tables S2/S3.
Sources
spliceai ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS3 No functional data available for this intronic variant. SpliceAI predicts no splice impact (max delta 0.0), but this is insufficient alone as well-established functional evidence in either direction. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice alteration.
Still missing
  • No published functional studies for this specific variant.
Sources
spliceai ↗
PM6 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP4 No phenotype or family history data specific to this variant are available. Details ▾Hide ▴
Still missing
  • No detailed phenotype data available for individuals carrying this variant.
BS2 No data available on observation of this variant in healthy adults with expected full-penetrance early-onset disease, either in trans with a pathogenic variant or in homozygous state. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers.
BS3 No well-established functional studies demonstrate no damaging effect for this specific variant. SpliceAI max delta 0.0 alone is insufficient to meet BS3. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice effect
  • but alone insufficient for BS3.
Still missing
  • No published functional assays for this variant.
Sources
spliceai ↗
BS4 No segregation data available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP2 No data available on observation of this variant in trans with a known pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No data available on an alternative molecular basis for disease in cases carrying this variant. Details ▾Hide ▴
Still missing
  • No data on alternative molecular diagnoses.
BP6 No data available from a reputable source classifying this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Likely benign from a single submitter
  • not sufficient alone without supporting evidence review.
Still missing
  • No expert panel or multi-submitter benign classification.
PS5 No data available to assess this criterion. Details ▾Hide ▴
Still missing
  • No established pathogenic variant at same codon.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant (c.6748-18G>A, intron 48); not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 framework not applicable. Details ▾Hide ▴
Evidence considered
  • Intronic variant with no predicted protein truncation or canonical splice disruption.
PS1 N/ANo known pathogenic variant has been established at this same nucleotide position to support PS1. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant identified at c.6748-18 in ClinVar or literature.
PS4 N/ACustom León-Castillo PS4 rule applies only to specific recurrent missense variants in endometrial carcinoma cohorts (Table S1) with combined EC count ≥10. This is an intronic variant absent from the supplementary tables; no germline case-control data available. Details ▾Hide ▴
Evidence considered
  • Variant is intronic and not represented in León-Castillo Table S1.
PM1 N/ACustom León-Castillo PM1 rules apply only to specific missense variants in the POLE exonuclease domain. This is an intronic variant (c.6748-18G>A, intron 48) outside the exonuclease domain and outside the scope of the custom framework. Details ▾Hide ▴
Evidence considered
  • Intronic variant not in exonuclease domain
  • not among the established hotspot or recurrent missense variants.
PM5 N/AIntronic variant; cannot establish same-residue missense comparator. PM5 candidate harvesting returned no eligible comparators. Details ▾Hide ▴
Evidence considered
  • No protein-level consequence
  • PM5 semantics not applicable to intronic variants.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • PP2 missense-specific.
PP5 N/AClinVar reports this variant as Likely benign (single submitter, criteria provided). PP5 requires a reputable source reporting the variant as pathogenic; the available classification is benign-leaning. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (VCV001540941
  • SCV002332903
  • Invitae).
Sources
clinvar ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is an intronic variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP1 missense-specific.
BP3 N/ANot an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splice impact. This is an intronic variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 synonymous-specific.

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.6748-18G>A
Protein (HGVS p.)
NP_006222.2:p.?
GRCh38
chr12:132624828 C>T
GRCh37
chr12:133201414 C>T
ClinVar
1540941

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 13 / 1,594,924 alleles AF 8.15e-06 · 0 homozygotes · FAF 5.44e-05
gnomAD v2.1 8 / 249,726 alleles AF 3.2e-05 · 0 homozygotes · FAF 7.54e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 8.2e-06 · 13 / 1,594,924 alleles · 0 hom · FAF 5.4e-05
Middle Eastern1 / 6,026 0.00017
Admixed American7 / 59,972 0.00012
African/African American3 / 74,612 4e-05
Remaining individuals2 / 61,860 3.2e-05
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, European (non-Finnish).

gnomAD v2.1

AF 3.2e-05 · 8 / 249,726 alleles · 0 hom · FAF 7.5e-05
Remaining individuals2 / 6,112 0.00033
Admixed American6 / 34,412 0.00017
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.15086e-06; MAF= 0.00082%, 13/1594924 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165948; MAF= 0.01659%, 1/6026 alleles, homozygotes = 0); grpmax FAF= 5.436e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.20351e-05; MAF= 0.00320%, 8/249726 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000327225; MAF= 0.03272%, 2/6112 alleles, homozygotes = 0); grpmax FAF= 7.539e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +154 bp
0.000
SpliceAI acceptor gainat -33 bp
0.000
SpliceAI donor lossat +424 bp
0.000
SpliceAI donor gainat +74 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no splice impact (max delta 0.0). REVEL and BayesDel scores are not available for this intronic variant. The variant is absent from León-Castillo supplementary Tables S2 and S3. No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice alteration.
  • REVEL and BayesDel not available (intronic variant).
  • Variant absent from León-Castillo Tables S2/S3.
Sources
spliceai ↗
BP4 SpliceAI predicts no splice impact (max delta 0.0), but multiple lines of computational evidence are not available for this intronic variant. REVEL and BayesDel are not applicable. The variant is absent from León-Castillo Tables S2/S3. Insufficient computational evidence to meet BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.0 — no predicted splice alteration.
  • REVEL and BayesDel not available (intronic).
  • Variant absent from León-Castillo Tables S2/S3.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splice impact. This is an intronic variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 synonymous-specific.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Describes the Sherloc classification framework, a refinement of ACMG-AMP variant classification criteria. This is a methodology paper that does not discuss POLE or NM_006231.4:c.6748-18G>A.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 13 / 1,594,924 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗

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= 8.15086e-06; MAF= 0.00082%, 13/1594924 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165948; MAF= 0.01659%, 1/6026 alleles, homozygotes = 0); grpmax FAF= 5.436e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.20351e-05; MAF= 0.00320%, 8/249726 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000327225; MAF= 0.03272%, 2/6112 alleles, homozygotes = 0); grpmax FAF= 7.539e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1540941)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Somatic

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