Variant classification summary

NM_006231.4:c.2083T>C

POLE · NP_006222.2:p.(Phe695Leu) · NM_006231.4

GRCh37: chr12:133245032 A>G · GRCh38: chr12:132668446 A>G

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2_Supporting BP4_Supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Phe695Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The POLE c.2083T>C (p.Phe695Leu; p.F695L) variant has not been identified as a recurrent POLE hotspot in the León-Castillo endometrial carcinoma datasets or Cancer Hotspots and has been reported in ClinVar mainly as uncertain significance, with some likely benign submissions.

2

This variant is rare in population databases, with an allele frequency of 0.00320% in gnomAD v2.1 and 0.00329% in gnomAD v4.1, both below the project's 0.1% PM2 threshold.

3

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact (maximum delta score 0.08), REVEL is 0.322, and BayesDel is -0.367686.

Final determination: PM2_Supporting and BP4_Supporting are present, but this evidence combination does not meet the framework thresholds for pathogenic, likely pathogenic, benign, or likely benign classification; therefore the variant is classified as uncertain significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical +/-1,2 splice variant.	pvs1_variant_assessment pvs1_generic_framework pvs1_gene_context
PS1	Not assessed	No evidence was identified showing a different nucleotide change that produces the same POLE p.Phe695Leu protein change and is already established as pathogenic or likely pathogenic.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified.
PS3	Not assessed	No variant-specific functional study demonstrating a damaging effect for p.Phe695Leu was identified in the reviewed evidence.	oncokb
PS4	Not met	The local POLE framework applies PS4 only to exact variants that are recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with a combined count of at least 10 and that belong to the established pathogenic hotspot set. p.Phe695Leu was not identified in the León-Castillo recurrent-variant table and is not part of the established hotspot set, so this criterion is not met.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM1	Not met	The local POLE framework does not award PM1 simply for being in POLE. It is limited to specific exact exonuclease-domain hotspot or recurrent pathogenic substitutions from León-Castillo et al. p.Phe695Leu is not one of the framework-listed hotspot or recurrent pathogenic substitutions, and Cancer Hotspots did not identify this residue as a statistically significant hotspot.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002 hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00320% (9/281330), and in gnomAD v4.1 it is 0.00329% (53/1612366), both well below the project's non-VCEP PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with pathogenic variants observed in trans, and that evidence context was not applicable here.
PM4	N/A	This is not a protein length-changing variant, so PM4 does not apply.
PM5	Not assessed	No evidence was identified that a different missense change at codon 695 is established as pathogenic or likely pathogenic for use as PM5.	clinvar vcep_path_250_323_s002
PM6	Not assessed	No assumed de novo occurrence data were identified.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	The reviewed evidence did not establish a gene-specific PP2 rule showing that POLE is a gene in which missense variation is a common mechanism with low background benign missense variation across the full protein.	final_classification_framework
PP3	Not met	The local POLE computational rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; these results do not support a deleterious computational effect.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai revel bayesdel
PP4	Not assessed	No phenotype information was provided that is sufficiently specific for a POLE-related hereditary syndrome to support PP4.
PP5	N/A	PP5 is not used as an independent criterion because source-based assertions alone are not accepted as primary evidence here.	clinvar
BA1	Not met	This variant does not meet the benign stand-alone frequency threshold. The highest observed gnomAD population frequency is 0.01646% in gnomAD v4.1, which is well below the project's BA1 threshold of 1%.	gnomad_v4 gnomad_v2
BS1	Not met	This variant does not meet the strong benign frequency threshold. The highest observed gnomAD population frequency is 0.01646%, which is below the project's BS1 threshold of 0.3%.	gnomad_v4 gnomad_v2
BS2	Not assessed	The reviewed evidence did not establish a validated BS2 framework for this hereditary cancer context, and the absence of homozygotes alone is not sufficient to use BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No variant-specific functional study showing normal or near-normal POLE function was identified.	oncokb
BS4	Not assessed	No evidence showing lack of segregation with disease was identified.
BP1	N/A	BP1 does not apply because missense variation is an established disease-relevant variant class in POLE.	final_classification_framework vcep_path_250_323
BP2	Not assessed	No phase or co-occurrence data were identified to support or refute BP2.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, so BP3 does not apply.
BP4	Met	The local POLE BP4 rule cannot be used because p.Phe695Leu was not identified in the León-Castillo supplementary in silico tables. Under generic computational review, SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, REVEL is 0.322, and BayesDel is -0.367686; taken together, the available computational evidence argues against a damaging effect.	final_classification_framework vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or independent explanation for disease was provided for assessment under BP5.
BP6	N/A	BP6 is not used as an independent criterion because source-based assertions alone are not accepted as primary evidence here.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or intronic change predicted to have no splice impact, so BP7 does not apply.	spliceai

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