POLEc.5811+16T>CBenign

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Variant interpretation report

POLE c.5811+16T>C, p.?

NM_006231.4:c.5811+16T>C NP_006222.2:p.? View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

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 stand alone (benign) · 2 supporting (benign)
Expert rules: León-Castillo et al. 2020 custom POLE framework
Other laboratories (ClinVar): 4 Likely benign · 3 Benign
Pipeline record: 7 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

BA1 (stand alone): This variant has an allele frequency of 1.41% in the African/African American subpopulation in gnomAD v2.1 (350/24,822 alleles, 4 homozygotes) and 1.42% in gnomAD v4.1 (1,056/74,594 alleles, 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27% (95% CI upper bound). All exceed the project threshold of >1% for BA1, indicating this variant is too common to be a pathogenic cause of a rare Mendelian disorder.
BS2 (supporting): This variant is observed in a homozygous state in 4 individuals in gnomAD v2.1 and 8 individuals in gnomAD v4.1, indicating it is present in healthy adults without apparent disease. Observation in homozygotes supports a benign interpretation for a rare disease gene.
BP4 (supporting): SpliceAI predicts no significant splice impact for this intronic variant (max delta = 0.01). Multiple in silico tools (REVEL, BayesDel) cannot be applied to an intronic variant. For a deep intronic substitution at position +16, the absence of a predicted splicing alteration constitutes computational evidence suggesting no impact on the gene product.

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: 0 Benign evidence criteria: 3

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3

BA1Stand alone

BA1 · stand alone

This variant has an allele frequency of 1.41% in the African/African American subpopulation in gnomAD v2.1 (350/24,822 alleles, 4 homozygotes) and 1.42% in gnomAD v4.1 (1,056/74,594 alleles, 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27% (95% CI upper bound). All exceed the project threshold of >1% for BA1, indicating this variant is too common to be a pathogenic cause of a rare Mendelian disorder.

BS2Supporting

BS2 · supporting

This variant is observed in a homozygous state in 4 individuals in gnomAD v2.1 and 8 individuals in gnomAD v4.1, indicating it is present in healthy adults without apparent disease. Observation in homozygotes supports a benign interpretation for a rare disease gene.

BP4Supporting

BP4 · supporting

SpliceAI predicts no significant splice impact for this intronic variant (max delta = 0.01). Multiple in silico tools (REVEL, BayesDel) cannot be applied to an intronic variant. For a deep intronic substitution at position +16, the absence of a predicted splicing alteration constitutes computational evidence suggesting no impact on the gene product.

Recorded classification: Benign

BA1 is met as a stand-alone benign criterion (gnomAD African/African American AF 1.41% in v2.1, 1.42% in v4.1, with homozygotes observed). Per both the León-Castillo 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules, BA1 alone is sufficient to classify the variant as Benign. BS2 (supporting benign, homozygotes in gnomAD) and BP4 (supporting benign, SpliceAI delta 0.01) provide additional benign evidence but are not required to reach the Benign call.

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

1,193 / 1,600,006 alleles

gnomAD v4.1: 1,193 / 1,600,006 alleles. Recorded AF 0.000745622. Recorded homozygote count 8.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00134183; MAF= 0.13418%, 370/275742 alleles, homozygotes = 4) and has highest observed frequency in the African/African American population (AF= 0.0141004; MAF= 1.41004%, 350/24822 alleles, homozygotes = 4); grpmax FAF= 0.0126994.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).

Applied · BA1, BS2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

7 reported laboratory submissions

4 Likely benign · 3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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.

26 criteria with recorded statuses: 3 met · 11 not met · 1 not assessed · 11 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 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_006231.4:c.5811+16T>C is an intronic substitution in POLE at position +16 of intron 42. SpliceAI predicts no significant splice impact (max delta = 0.01).

This variant is present in gnomAD at an allele frequency of 1.41% in the African/African American subpopulation in v2.1 (350/24,822 alleles, including 4 homozygotes) and 1.42% in v4.1 (1,056/74,594 alleles, including 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27%. All exceed the >1% BA1 threshold.

This variant is observed in a homozygous state in gnomAD (4 individuals in v2.1, 8 in v4.1), consistent with a benign interpretation for a gene associated with rare Mendelian disease (BS2).

Seven clinical laboratories in ClinVar classify this variant as Likely benign (4) or Benign (3). While the review status is single submitter and does not meet the 3-star expert panel threshold for PP5/BP6, the unanimous direction of clinical classifications is consistent with a benign interpretation.

BA1 as a stand-alone benign criterion is sufficient to classify this variant as Benign per ACMG/AMP 2015 combination rules.

Met · 3

BA1 Stand aloneThis variant has an allele frequency of 1.41% in the African/African American subpopulation in gnomAD v2.1 (350/24,822 alleles, 4 homozygotes) and 1.42% in gnomAD v4.1 (1,056/74,594 alleles, 8 homozygotes). The gnomAD v2.1 grpmax filtering allele frequency is 1.27% (95% CI upper bound). All exceed the project threshold of >1% for BA1, indicating this variant is too common to be a pathogenic cause of a rare Mendelian disorder. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 African/African American AF = 1.41% (350/24
822 alleles
4 homozygotes)
gnomAD v4.1 African/African American AF = 1.42% (1
056/74
594 alleles
8 homozygotes)
gnomAD v2.1 grpmax FAF = 1.27%
gnomAD v4.1 grpmax FAF = 1.34%
Observed in homozygous state in both gnomAD versions (4-8 homozygotes)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 SupportingThis variant is observed in a homozygous state in 4 individuals in gnomAD v2.1 and 8 individuals in gnomAD v4.1, indicating it is present in healthy adults without apparent disease. Observation in homozygotes supports a benign interpretation for a rare disease gene. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 4 homozygotes
gnomAD v4.1: 8 homozygotes
Homozygous state seen across two independent gnomAD releases

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingSpliceAI predicts no significant splice impact for this intronic variant (max delta = 0.01). Multiple in silico tools (REVEL, BayesDel) cannot be applied to an intronic variant. For a deep intronic substitution at position +16, the absence of a predicted splicing alteration constitutes computational evidence suggesting no impact on the gene product. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.01 (no significant splice impact at donor/acceptor sites within ±50 bp)
REVEL not applicable (intronic
no missense change)
BayesDel not applicable (intronic

Sources

spliceai ↗

Not met · 11 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. Details ▾Hide ▴

Still missing

No de novo testing data available

PM2 This variant is present in gnomAD v2.1 at an overall allele frequency of 0.134% (370/275,742 alleles), exceeding the 0.1% PM2 threshold. It is not absent from the general population. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF = 0.134% (370/275
742 alleles
4 homozygotes)
gnomAD v4.1: AF = 0.075% (1
193/1
600
006 alleles
8 homozygotes)

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM6 No de novo data are available for this variant. Details ▾Hide ▴

Still missing

No de novo testing data available

PP1 No segregation data are available for this variant. Details ▾Hide ▴

Still missing

No co-segregation data available

PP3 SpliceAI predicts no significant splice impact (max delta = 0.01). The León-Castillo 2020 custom PP3 rule applies only to missense variants in Supplementary Tables S2/S3. No in silico tool (REVEL, BayesDel, HCI prior) returns a score for this intronic variant. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.01 (no significant splice impact)
REVEL not available for intronic variant
BayesDel not available for intronic variant
HCI prior: gene not supported
Variant absent from Supplementary Tables S2 and S3

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

PP5 ClinVar classifies this variant as Likely benign (4 laboratories) and Benign (3 laboratories) with review status 'criteria provided, single submitter.' This does not meet the 3-star expert panel threshold required for PP5 application. Seven clinical laboratories independently classify this as benign or likely benign, which is consistent with a benign interpretation. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 371907: Likely benign (4 labs)
Benign (3 labs)
Review status: criteria provided
single submitter (not 3-star expert panel)

Sources

clinvar ↗

BS1 The overall allele frequency in gnomAD v2.1 is 0.134% (370/275,742 alleles), which is below the 0.3% BS1 threshold. The variant is not sufficiently common at the overall population level to meet BS1, though it is concentrated in the African/African American subpopulation. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 overall AF = 0.134% — below 0.3% threshold
gnomAD v4.1 overall AF = 0.075% — below 0.3% threshold

Sources

gnomad_v2 ↗

BS4 No segregation data are available to demonstrate lack of segregation with disease. Details ▾Hide ▴

Still missing

No segregation data available

BP2 No data are available regarding observation in trans with a pathogenic variant. Details ▾Hide ▴

Still missing

No data about observation in trans with a pathogenic variant

BP5 No data available regarding an alternate molecular basis for disease in affected individuals harboring this variant. Details ▾Hide ▴

Still missing

No data on alternate molecular basis

BP6 ClinVar classifies this variant as Likely benign (4 laboratories) and Benign (3 laboratories) with review status 'criteria provided, single submitter.' This does not meet the 3-star expert panel threshold required for BP6 application. Seven clinical laboratories independently support a benign or likely benign classification. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 371907: Likely benign (4 labs)
Benign (3 labs)
Review status: criteria provided
single submitter (not 3-star expert panel)

Sources

clinvar ↗

Not assessed · 1 · no assessment recorded

PP4 No phenotype specificity data are available to assess whether this variant's phenotype is specific for the gene/disease. Details ▾Hide ▴

Still missing

No phenotype specificity data available

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis variant (NM_006231.4:c.5811+16T>C) is an intronic substitution at position +16 of intron 42, not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 generic framework does not apply. Details ▾Hide ▴

Evidence considered

Intronic variant at +16 of intron 42
does not fall into any PVS1 null-variant bucket
No canonical splice consensus disruption ±1
2

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PS1 N/APS1 applies when a different pathogenic missense change at the same amino acid residue exists. This is an intronic variant with no amino acid change. Details ▾Hide ▴

No further detail was recorded.

PS3 N/AThis is a deep intronic substitution (c.5811+16T>C) with no predicted protein consequence. No functional studies address this variant and no systematic functional characterization of this intronic region is available. Details ▾Hide ▴

Evidence considered

Intronic variant with no predicted protein change
SpliceAI predicts no splicing impact (delta 0.01)

PS4 N/AThe custom León-Castillo 2020 PS4 rule applies only to specific recurrent POLE missense hotspot variants in endometrial carcinoma cohorts. This intronic variant is not a missense change and is absent from the supplementary recurrence tables. Details ▾Hide ▴

Evidence considered

Variant absent from Supplementary Table S1 (recurrent POLE variants in COSMIC/TCGA EC cohorts)
Custom PS4 rule is restricted to missense hotspot variants

Sources

vcep_path_250_323_s002

PM1 N/AThe León-Castillo 2020 custom PM1 framework applies only to specific POLE missense variants within the exonuclease domain. This is an intronic variant and is not eligible. Details ▾Hide ▴

Evidence considered

Custom PM1 rules restricted to missense exonuclease-domain variants
Variant is intronic at position c.5811+16

Sources

vcep_path_250_323

PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This is an intronic variant with no amino acid residue; PM5 candidate harvesting confirms not applicable. Details ▾Hide ▴

Evidence considered

pm5_candidates.json: eligible_for_classic_pm5_search = false
unable to parse missense residue context

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes where missense variants are a common disease mechanism. This is an intronic substitution. Details ▾Hide ▴

No further detail was recorded.

BS3 N/AThis is an intronic variant with SpliceAI predicting no splice impact (delta 0.01). No functional studies that demonstrate no deleterious effect exist for this variant. Details ▾Hide ▴

Evidence considered

Intronic variant with no predicted protein consequence
SpliceAI delta 0.01: no splicing impact

Sources

spliceai ↗

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is an intronic substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact. This is an intronic substitution (c.5811+16T>C), not a synonymous coding variant, and does not fit the BP7 criterion definition. Details ▾Hide ▴

Evidence considered

Variant is intronic at +16
not synonymous

Sources

PMID:25741868 ↗

PS5 N/APS5 requires an established pathogenic variant at the same amino acid residue. This is an intronic variant with no amino acid change. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: POLE
Transcript: NM_006231.4
Coding (HGVS c.): NM_006231.4:c.5811+16T>C
Protein (HGVS p.): NP_006222.2:p.?
GRCh38: chr12:132635876 A>G
GRCh37: chr12:133212462 A>G
ClinVar: 371907

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 1,193 / 1,600,006 alleles AF 0.000746 · 8 homozygotes · FAF 0.0134

gnomAD v2.1 370 / 275,742 alleles AF 0.00134 · 4 homozygotes · FAF 0.0127

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00075 · 1193 / 1,600,006 alleles · 8 hom · FAF 0.013

African/African American1056 / 74,594	0.0148 hom
Remaining individuals64 / 61,862	0.001
Admixed American45 / 58,290	0.00077
Middle Eastern2 / 5,990	0.00033
East Asian1 / 44,606	2.2e-05
European (non-Finnish)25 / 1,171,058	2.1e-05

0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0013 · 370 / 275,742 alleles · 4 hom · FAF 0.013

African/African American350 / 24,822	0.0144 hom
Admixed American17 / 33,768	0.0005
Remaining individuals2 / 7,006	0.00029
European (non-Finnish)1 / 126,330	7.9e-06

0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000745622; MAF= 0.07456%, 1193/1600006 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0141566; MAF= 1.41566%, 1056/74594 alleles, homozygotes = 8); grpmax FAF= 0.013447.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +100 bp

0.000

SpliceAI acceptor gainat +47 bp

0.010

SpliceAI donor lossat +246 bp

0.000

SpliceAI donor gainat -489 bp

0.010

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 = 0.01 (no significant splice impact at donor/acceptor sites within ±50 bp)
REVEL not applicable (intronic
no missense change)
BayesDel not applicable (intronic

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.01 (no significant splice impact)
REVEL not available for intronic variant
BayesDel not available for intronic variant
HCI prior: gene not supported
Variant absent from Supplementary Tables S2 and S3

Sources

spliceai ↗vcep_path_250_323_s003vcep_path_250_323_s004

Evidence considered

Variant is intronic at +16
not synonymous

Sources

PMID:25741868 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

3 paper records 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015

This is the ACMG/AMP 2015 standards and guidelines paper for interpretation of sequence variants. NM_006231.4:c.5811+16T>C is not mentioned or discussed.
Does not name this variant
PMID 25741868 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

Hampel H et al. · 2015

This is a practice guideline on referral indications for cancer predisposition assessment. NM_006231.4:c.5811+16T>C is not mentioned.
Does not name this variant
PMID 25394175 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

This is the Sherloc refinement of ACMG-AMP variant classification criteria. NM_006231.4:c.5811+16T>C is not mentioned.
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 1,193 / 1,600,006 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 4 Likely benign · 3 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

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (3 clinical laboratories). (ClinVarID = 371907)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Somatic

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