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).1 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.2 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).3 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.4 BA1 as a stand-alone benign criterion is sufficient to classify this variant as Benign per ACMG/AMP 2015 combination rules.5
POLE
Final classification
Benign
POLE c.5811+16T>C · p.?
POLE
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).
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.
Classification rationale
BA1BS2BP4
Benign
POLE c.5811+16T>C
BA1 + BS2 + BP4
→
Benign
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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.
gnomAD v2.1 African/African American AF = 1.41% (350/24822 alleles4 homozygotes)
✓
BS2
supporting
Benign
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.
gnomAD v2.1: 4 homozygotesgnomAD v4.1: 8 homozygotesHomozygous state seen across two independent gnomAD releases
✓
BP4
supporting
Benign
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.
SpliceAI max delta = 0.01 (no significant splice impact at donor/acceptor sites within ±50 bp)REVEL not applicable (intronicno missense change)
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
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.
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta = 0.01).
PP4
No phenotype specificity data are available to assess whether this variant's phenotype is specific for the gene/disease.
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.
Benign
BS1
The overall allele frequency in gnomAD v2.1 is 0.134% (370/275,742 alleles), which is below the 0.3% BS1 threshold.
BS4
No segregation data are available to demonstrate lack of segregation with disease.
BP2
No data are available regarding observation in trans with a pathogenic variant.
BP5
No data available regarding an alternate molecular basis for disease in affected individuals harboring this variant.
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.
N/A · 10
PVS1 · PS1 · PS3 · PS4 · PM1 · PM5 · PP2 · BS3 · BP1 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.075%
· 1193 / 1,600,006
8 hom · FAF 1.3%
8 hom · FAF 1.3%
African/African American 1056 / 74,594 |
1.4% 8 hom |
Remaining individuals 64 / 61,862 |
0.1% |
Admixed American 45 / 58,290 |
0.077% |
Middle Eastern 2 / 5,990 |
0.033% |
East Asian 1 / 44,606 |
0.0022% |
European (non-Finnish) 25 / 1,171,058 |
0.0021% |
+ 4 not observed (European (Finnish), Amish, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.13%
· 370 / 275,742
4 hom · FAF 1.3%
4 hom · FAF 1.3%
African/African American 350 / 24,822 |
1.4% 4 hom |
Admixed American 17 / 33,768 |
0.05% |
Remaining individuals 2 / 7,006 |
0.029% |
European (non-Finnish) 1 / 126,330 |
0.00079% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
0.065%
· 12 / 18,418
0 hom · FAF 0.6%
0 hom · FAF 0.6%
African/African American 11 / 1,020 |
1.1% |
European (non-Finnish) 1 / 11,738 |
0.0085% |
+ 7 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
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).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗
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.
CLINVAR
25394175 ↗
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.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR