NM_006231.4:c.6150C>A (p.Phe2050Leu) is a missense variant in the C-terminal region of POLE, far outside the exonuclease domain (residues ~268-471) where established pathogenic hotspot mutations cluster.1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).2 Multiple lines of computational evidence (REVEL 0.228, BayesDel -0.046, SpliceAI max delta 0.15) suggest no significant impact on the gene product (BP4_Supporting).3 ClinVar reports this variant as Uncertain significance (VariationID 3004425) with review status 'criteria provided, single submitter' (1-star); no expert panel classification is available.4 No published functional studies, segregation analyses, de novo observations, or case-control data exist for this variant.5 The variant has not been observed in COSMIC and is not listed as a recurrent variant in the Leon-Castillo et al. 2020 endometrial carcinoma cohort analysis.6 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient for classification; the variant remains a Variant of Uncertain Significance.
POLE
Final classification
VUS
POLE c.6150C>A · p.Phe2050Leu
POLE
NM_006231.4:c.6150C>A (p.Phe2050Leu) is a missense variant in the C-terminal region of POLE, far outside the exonuclease domain (residues ~268-471) where established pathogenic hotspot mutations cluster.
Only two criteria were met: PM2_Supporting (absent from gnomAD v2.1, v4.1, and gnomAD-Canada) and BP4_Supporting (concordant benign in silico predictions: REVEL 0.228, BayesDel -0.046, SpliceAI max delta 0.15). This combination of one supporting pathogenic criterion and one supporting benign criterion does not satisfy any pathogenic, likely pathogenic, likely benign, or benign combination rule under the ACMG/AMP 2015 framework. The default classification is Variant of Uncertain Significance.
Classification rationale
PM2
BP4
VUS
POLE c.6150C>A
PM2 + BP4
→
VUS
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_006231.4:c.6150C>A is absent from all large population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. This satisfies PM2_Supporting under the generic ACMG/AMP framework (allele frequency <0.1% and absent from controls).
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.228 (below the 0.3 benign-leaning threshold), BayesDel score is -0.046 (negative, consistent with a benign prediction), and SpliceAI max delta score is 0.15 (below the 0.2 threshold for significant splice impact). The variant is absent from the Leon-Castillo et al. Supplementary Tables S2/S3, so the custom POLE BP4 rule is not triggered; generic ACMG/AMP BP4 applies at supporting strength based on concordant benign predictions from multiple algorithms.
REVEL score 0.228 — below the 0.3 benign-leaning threshold.BayesDel score -0.046 — negative scoreconsistent with benign prediction.
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant at the same nucleotide position (c.6150) with the same amino acid change (p.Phe2050Leu) has been identified.
PS2
No de novo observation has been reported for this variant.
PS3
No functional data exists for NM_006231.4:c.6150C>A (p.Phe2050Leu).
PS4
The variant is absent from COSMIC and was not identified in the TCGA endometrial carcinoma cohorts summarized in Leon-Castillo et al.
PM1
PM1 is not met.
PM5
No same-residue comparator variants with a pathogenic or likely pathogenic classification were identified for codon 2050.
PM6
No de novo observation has been reported for this variant.
PP1
No segregation data are available for this variant.
PP2
PP2 requires a low rate of benign missense variation and demonstration that missense variants are a common disease mechanism for the gene.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No specific phenotypic or family history data are available for this variant.
PP5
ClinVar reports this variant as Uncertain significance (VariationID 3004425) with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder.
BS3
No published functional studies have assessed NM_006231.4:c.6150C>A (p.Phe2050Leu) in a well-established assay demonstrating no deleterious effect.
BS4
No segregation data are available to assess non-segregation with disease.
BP1
BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease.
BP2
BP2 requires observation of the variant in trans with a known pathogenic variant in a gene for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder.
BP5
BP5 requires observation of the variant in a case with an alternative molecular cause of disease.
BP6
BP6 requires a reputable source to report the variant as benign.
N/A · 2
PVS1 · 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
Absent from gnomAD-Canada v1.0.
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 (2 clinical laboratories). (ClinVarID = 3004425)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.228. BayesDel score = -0.0463543.
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 · 2 PMIDs not cited in assessment
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