NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain. The variant is absent from gnomAD v2.1 (exomes) and v4.1 (exomes) population databases, meeting PM2 at moderate strength (PM2_Moderate).1 Multiple in silico tools predict a benign impact: REVEL score 0.267 (benign-leaning, below the 0.5 pathogenic threshold), BayesDel score -0.221 (benign), and SpliceAI max delta 0.06 (no splice impact). This meets BP4 at supporting benign strength (BP4_Supporting).2 The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories (Variation ID 405767). It is not among the established POLE exonuclease-domain hotspot mutations identified by León-Castillo et al. 2020, and is absent from COSMIC and Cancer Hotspots.3 With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. The variant is classified as Variant of Uncertain Significance (VUS) under the León-Castillo et al. 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.4
POLE
Final classification
VUS
POLE c.1708C>A · p.Leu570Met
POLE
NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain.
The León-Castillo et al. 2020 custom POLE framework (gene_framework) was applied. Only one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met. No pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied. Per the framework (which mirrors generic ACMG/AMP 2015 combination logic), all other combinations default to Uncertain Significance.
Classification rationale
PM2
BP4
VUS
POLE c.1708C>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
3
clinvar ↗vcep_path_250_323_s002
4
final_classification_frameworkgeneric_acmg_combination_rules
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
NM_006231.4:c.1708C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the PM2 criterion (allele frequency <0.1% in large population databases).
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.267 (below the 0.5 pathogenic threshold, in benign-leaning range), BayesDel score is -0.221 (negative, predicting benign impact), and SpliceAI predicts no splicing alteration (max delta score 0.06). The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al. 2020, so the custom POLE BP4 rule does not apply; this assessment uses the generic ACMG/AMP BP4 criterion based on the converging in silico evidence.
REVEL: 0.267 (benign-leaning).BayesDel: -0.221 (benign).SpliceAI: max delta 0.06 (no impact).
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant with a different nucleotide change producing the same amino acid substitution (p.Leu570Met) has been identified at this codon.
PS2
No de novo data available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for NM_006231.4:c.1708C>A (p.Leu570Met).
PS4
NM_006231.4:c.1708C>A (p.Leu570Met) is absent from both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1 of León-Castillo et al.
PM1
p.Leu570Met (residue 570) is not one of the five established POLE exonuclease-domain hotspot variants (P286R, V411L, S297F, A456P, S459F) per the León-Castillo et al.
PM5
No pathogenic missense variant at the same codon (Leu570) with a different amino acid change was identified through ClinVar candidate harvesting or the León-Castillo supplementary tables.
PM6
No de novo data available for this variant.
PP1
No co-segregation data available for this variant in affected families.
PP2
No HCI prior probability score or gene-level missense constraint metrics (z-score, pLI) are available for POLE to evaluate the rate of benign missense variation.
PP3
The variant is absent from Supplementary Tables S2 and S3 of León-Castillo et al.
PP4
No patient-specific phenotype or family history data are available for this case.
PP5
No reputable source has classified NM_006231.4:c.1708C>A as pathogenic.
Benign
BA1
NM_006231.4:c.1708C>A is absent from gnomAD v2.1 and v4.1.
BS1
NM_006231.4:c.1708C>A is absent from gnomAD v2.1 and v4.1.
BS2
No data available regarding observation of this variant in healthy adult individuals.
BS3
No well-established in vitro or in vivo functional studies have been identified showing no damaging effect for NM_006231.4:c.1708C>A.
BS4
No segregation data are available to evaluate lack of co-segregation with disease.
BP2
No data available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No data available regarding identification of an alternate molecular basis for disease in a case carrying this variant.
BP6
No reputable source has classified NM_006231.4:c.1708C>A as benign.
N/A · 3
PVS1 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 405767)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.267. BayesDel score = -0.220802.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant 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