POLEc.3459+12G>TUncertain significance

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Variant interpretation report

POLE c.3459+12G>T, p.?

NM_006231.4:c.3459+12G>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.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: León-Castillo et al. 2020 custom POLE framework
Other laboratories (ClinVar): 1 Likely benign
Pipeline record: 6 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): Extremely low allele frequency in population databases. Present at AF=1.24e-6 (2/1,614,094 alleles) in gnomAD v4.1 and absent from gnomAD v2.1. Well below the 0.1% PM2 threshold. No homozygotes observed.
BP7 (supporting): Intronic variant at c.3459+12, 12 bases downstream of exon 28, outside the canonical splice site consensus region. SpliceAI predicts no splicing impact (max delta=0.0, no cryptic splice site creation). Per ClinGen SVI guidance, BP7 can be applied to intronic variants beyond the +7 position when splicing prediction tools show no effect.

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

PM2Supporting

PM2 · supporting

Extremely low allele frequency in population databases. Present at AF=1.24e-6 (2/1,614,094 alleles) in gnomAD v4.1 and absent from gnomAD v2.1. Well below the 0.1% PM2 threshold. No homozygotes observed.

Benign criteria applied · 1

BP7Supporting

BP7 · supporting

Intronic variant at c.3459+12, 12 bases downstream of exon 28, outside the canonical splice site consensus region. SpliceAI predicts no splicing impact (max delta=0.0, no cryptic splice site creation). Per ClinGen SVI guidance, BP7 can be applied to intronic variants beyond the +7 position when splicing prediction tools show no effect.

Recorded classification: Uncertain significance

Only two criteria met: PM2 at supporting strength (extremely rare in gnomAD, AF=1.24e-6) and BP7 at supporting benign strength (intronic +12, SpliceAI delta=0.0). No other pathogenic or benign criteria met. This constitutes conflicting evidence (1 supporting pathogenic + 1 supporting benign) and does not satisfy the threshold for any classified category under the standard ACMG/AMP 2015 combination rules used by the local POLE framework. Falls 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

2 / 1,614,094 alleles

gnomAD v4.1: 2 / 1,614,094 alleles. Recorded AF 1.23909e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from 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.

Applied · BP7 → SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 Likely benign. ClinVar API review status: criteria provided, single submitter.

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: 2 met · 11 not met · 6 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_006231.4:c.3459+12G>T is a rare intronic variant in POLE located 12 bases downstream of exon 28.

This variant is extremely rare in population databases, present at an allele frequency of 1.24e-6 (2/1,614,094 alleles) in gnomAD v4.1 and absent from gnomAD v2.1 (PM2_Supporting).

SpliceAI predicts no splicing impact (max delta=0.0), and the variant lies outside the canonical splice consensus at the +12 intronic position (BP7_Supporting).

This variant has been reported in ClinVar as Likely Benign by a single clinical laboratory (VariationID 1580883, 1-star review status), though the 1-star rating is insufficient for PP5 or BP6 application.

No functional data, segregation data, de novo reports, or case-control evidence are available for this variant. The León-Castillo et al. 2020 custom POLE framework is exclusively missense-focused and does not provide applicable rules for this intronic variant.

The variant has not been reported in somatic cancers (COSMIC) and is not a known hotspot (cancerhotspots.org negative).

With PM2_Supporting (pathogenic) and BP7_Supporting (benign), the evidence is conflicting and insufficient to reach a likely benign or likely pathogenic classification. This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingExtremely low allele frequency in population databases. Present at AF=1.24e-6 (2/1,614,094 alleles) in gnomAD v4.1 and absent from gnomAD v2.1. Well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF=1.24e-6 (2/1
614
094 alleles
0 homozygotes)
gnomAD v2.1: absent
grpmax FAF=2.8e-7

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP7 SupportingIntronic variant at c.3459+12, 12 bases downstream of exon 28, outside the canonical splice site consensus region. SpliceAI predicts no splicing impact (max delta=0.0, no cryptic splice site creation). Per ClinGen SVI guidance, BP7 can be applied to intronic variants beyond the +7 position when splicing prediction tools show no effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0
no acceptor gain/loss
no donor gain/loss
Intronic position +12 is beyond the +7 threshold for BP7 extension

Still missing

Nucleotide conservation at this position was not assessed
BP7 formally requires low conservation for synonymous variants
Extension of BP7 to deep intronic variants is not in the original 2015 ACMG/AMP guideline but is supported by ClinGen SVI recommendations

Sources

spliceai ↗

Not met · 11 · evaluated, threshold not reached

PS2 No de novo evidence identified for this variant. The only literature source (PMID:28492532) is a methods paper that does not report any patient-level data for this variant. Details ▾Hide ▴

Evidence considered

No de novo reports found in literature or ClinVar submissions

Still missing

No de novo testing data available

PS3 No functional assay data exists for this intronic variant. The León-Castillo et al. 2020 framework and supplementary tables are exclusively missense-focused. SpliceAI predicts no splicing effect (delta=0.0), indicating this variant is unlikely to be functional. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0
variant is intronic at +12 with no predicted splice effect
León-Castillo framework is missense-only

Still missing

No variant-specific functional studies available

Sources

spliceai ↗vcep_path_250_323

PS4 Variant is absent from COSMIC and not present in the León-Castillo et al. 2020 recurrent variant table (Supplementary Table S1, missense-only). No germline case-control enrichment data available. Custom PS4_Supporting rule requires exact missense variant recurrence in both COSMIC and TCGA EC cohorts with combined count >=10. Details ▾Hide ▴

Evidence considered

COSMIC: no record found
León-Castillo Table S1: missense-only
intronic variant not represented

Still missing

No case-control data for this variant

Sources

vcep_path_250_323_s002

PP3 No computational evidence supports a deleterious effect. SpliceAI delta=0.0 predicts no splicing impact. REVEL and BayesDel unavailable for intronic variants. The León-Castillo custom PP3 rule applies only to missense variants present in Supplementary Tables S2/S3. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0
REVEL: not found (intronic)
BayesDel: not found (intronic)
HCI prior: not found (gene not supported)

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

PP5 ClinVar classification is Likely Benign, not Pathogenic. Review status is 1-star (criteria provided, single submitter), which is below the 3-star expert panel threshold required for PP5. Additionally, PP5 requires a pathogenic assertion — the only ClinVar submission asserts Likely Benign. Details ▾Hide ▴

Evidence considered

ClinVar VariationID 1580883: Likely Benign
criteria provided single submitter (1-star)
Submitter: Labcorp Genetics (formerly Invitae)

Sources

clinvar ↗

BA1 Allele frequency is 1.24e-6 (0.00012%) in gnomAD v4.1, well below the 1% BA1 threshold. Absent from gnomAD v2.1. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF=1.24e-6 (0.00012%)
gnomAD v2.1 AF=0

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Allele frequency is 1.24e-6 (0.00012%) in gnomAD v4.1, well below the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF=1.24e-6 (0.00012%)
gnomAD v2.1 AF=0

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No homozygotes observed in gnomAD v4.1 or v2.1. No evidence of homozygous or biallelic occurrence in controls. Details ▾Hide ▴

Evidence considered

gnomAD homozygotes = 0 across all datasets

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No well-established functional studies demonstrate no damaging effect for this specific variant. SpliceAI prediction is computational, not a functional assay. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies identified
SpliceAI delta=0.0 is in silico
not functional assay

Still missing

No functional assay data for this variant

Sources

spliceai ↗

BP4 Only one line of computational evidence (SpliceAI delta=0.0) is available. BP4 requires multiple lines of computational evidence suggesting no impact. REVEL and BayesDel are unavailable for intronic variants. The León-Castillo custom BP4 rule applies only to missense variants in Tables S2/S3. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.0 (single tool)
REVEL: not available (intronic)
BayesDel: not available (intronic)
Custom framework BP4: missense-only

Still missing

Insufficient computational evidence — only one tool with result
need multiple lines for BP4

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

BP6 ClinVar classification is Likely Benign with 1-star review status (criteria provided, single submitter). BP6 requires a 3-star expert panel reputable source classification as benign. Single submitter does not meet the threshold. Details ▾Hide ▴

Evidence considered

ClinVar VariationID 1580883: Likely Benign
1-star (criteria provided
single submitter)
BP6 threshold: 3-star expert panel required

Sources

clinvar ↗

Not assessed · 6 · no assessment recorded

PM6 No de novo data available in the literature or ClinVar submissions for this variant. Cannot assess PM6 without variant-specific de novo confirmation. Details ▾Hide ▴

Evidence considered

No de novo reports identified

Still missing

No de novo data available

PP1 No segregation data available for this variant. Cannot assess co-segregation with disease in affected family members. Details ▾Hide ▴

Evidence considered

No segregation data available

Still missing

No family segregation data

PP4 No patient phenotype data provided for this case. Cannot assess whether the variant's phenotype is highly specific for a disease. Details ▾Hide ▴

Evidence considered

No phenotype data available

Still missing

Patient phenotype not provided

BS4 No segregation data available. Cannot assess lack of segregation in affected family members. Details ▾Hide ▴

Evidence considered

No segregation data available

Still missing

No family segregation data

BP2 No data on observation in trans with a known pathogenic variant. Cannot assess BP2. Details ▾Hide ▴

Evidence considered

No phase data available

Still missing

No trans observation data

BP5 No data on alternate molecular basis for disease. Cannot assess whether this variant was found in a case with a clear alternative explanation. Details ▾Hide ▴

Evidence considered

No alternate molecular basis data available

Still missing

No data on alternate molecular diagnosis

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AIntronic variant at c.3459+12, 12 bases downstream of exon 28. Not a nonsense, frameshift, or canonical ±1,2 splice site variant. PVS1 decision tree classifies this as 'other' and does not apply the generic null-variant framework. Details ▾Hide ▴

Evidence considered

PVS1 variant assessment: variant_bucket=other
apply_generic_pvs1_framework=false

Sources

pvs1_generic_framework ↗

PS1 N/AIntronic variant with no protein change; no amino acid residue to compare against known pathogenic missense variants at the same position. Details ▾Hide ▴

No further detail was recorded.

PM1 N/ACustom León-Castillo 2020 PM1 applies only to missense variants in the exonuclease domain. This is an intronic variant (c.3459+12G>T) that does not reside in a protein functional domain. No hotspot data (cancerhotspots.org negative). Details ▾Hide ▴

Evidence considered

Framework PM1 rules are missense-only
Hotspots: residue_significant=false
exact_variant_listed=no

Sources

vcep_path_250_323vcep_path_250_323_s002

PM5 N/AIntronic variant with no protein residue; unable to perform same-residue missense comparator search. PM5 candidate harvesting confirmed not applicable (eligible_for_classic_pm5_search=false). Details ▾Hide ▴

Evidence considered

PM5 candidates: found=false
reason=unable to confirm classic same-residue PM5 semantics

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation. This variant is intronic (c.3459+12G>T), not missense. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is intronic (c.3459+12G>T), not missense. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per instructions — trivially not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/AVariant does not alter an amino acid residue; cannot assess whether a different pathogenic missense change has been described at the same codon. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: POLE
Transcript: NM_006231.4
Coding (HGVS c.): NM_006231.4:c.3459+12G>T
Protein (HGVS p.): NP_006222.2:p.?
GRCh38: chr12:132657337 C>A
GRCh37: chr12:133233923 C>A
ClinVar: 1580883

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 2 / 1,614,094 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,614,094 alleles · 0 hom · FAF 2.8e-07

European (non-Finnish)2 / 1,179,994

1.7e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.23909e-06; MAF= 0.00012%, 2/1614094 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69492e-06; MAF= 0.00017%, 2/1179994 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -386 bp

0.000

SpliceAI acceptor gainat +208 bp

0.000

SpliceAI donor lossat -207 bp

0.000

SpliceAI donor gainat +398 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.0
no acceptor gain/loss
no donor gain/loss
Intronic position +12 is beyond the +7 threshold for BP7 extension

Still missing

Nucleotide conservation at this position was not assessed
BP7 formally requires low conservation for synonymous variants
Extension of BP7 to deep intronic variants is not in the original 2015 ACMG/AMP guideline but is supported by ClinGen SVI recommendations

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.0
REVEL: not found (intronic)
BayesDel: not found (intronic)
HCI prior: not found (gene not supported)

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

Evidence considered

SpliceAI max delta = 0.0 (single tool)
REVEL: not available (intronic)
BayesDel: not available (intronic)
Custom framework BP4: missense-only

Still missing

Insufficient computational evidence — only one tool with result
need multiple lines for BP4

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Methods paper describing a systematic variant classification framework. NM_006231.4:c.3459+12G>T was not identified in this paper.
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 2 / 1,614,094 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

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 Likely benign (1 clinical laboratory). (ClinVarID = 1580883)

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).