Variant classification summary

NM_006231.4:c.745C>A

POLE · NP_006222.2:p.(Arg249=) · NM_006231.4

GRCh37: chr12:133254005 G>T · GRCh38: chr12:132677419 G>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 BP7

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Arg249=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The POLE c.745C>A (p.Arg249=) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by two clinical laboratory submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1.

3

This variant is not listed among the recurrent or hotspot POLE exonuclease-domain substitutions in the León-Castillo POLE review materials.

4

This is a synonymous change outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.

Final determination: One moderate pathogenic criterion (PM2) and one supporting benign criterion (BP7) are present, and this combination does not meet thresholds for pathogenic, likely pathogenic, likely benign, or 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 synonymous substitution and is not a nonsense, frameshift, or canonical ±1,2 splice variant, so the generic PVS1 loss-of-function framework does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	This variant does not change the amino acid sequence, and no same-amino-acid pathogenic substitution basis for PS1 was identified.	clinvar
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant.
PS3	Not assessed	No published functional study was identified that directly tested this exact synonymous variant.	oncokb
PS4	Not met	This variant has not been reported in COSMIC and is not listed among the recurrent POLE endometrial carcinoma variants in Supplementary Table S1. The local POLE PS4 rule applies only to exact recurrent exonuclease-domain missense hotspot variants with combined COSMIC and TCGA endometrial carcinoma counts of at least 10, which is not met here.	vcep_path_250_323_s002 vcep_path_250_323 final_classification_framework
PM1	Not met	This synonymous variant is not one of the exact POLE exonuclease-domain hotspot or recurrent missense substitutions specified in the local POLE PM1 framework, and no statistically significant hotspot evidence was identified at Arg249.	vcep_path_250_323 vcep_path_250_323_s002 hotspots final_classification_framework
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0 in both datasets, which is below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	No trans configuration data or recessive-case evidence were identified for this variant.
PM4	N/A	This variant does not alter protein length or reading frame, so PM4 does not apply.	pvs1_variant_assessment
PM5	N/A	This criterion is for a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is synonymous, so PM5 does not apply.	clinvar
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is a missense criterion, and this variant is synonymous.	clinvar
PP3	N/A	The local POLE PP3 rule is restricted to exact missense variants represented in the León-Castillo supplementary in silico tables. This synonymous variant is not listed in those tables, REVEL and BayesDel scores were not available, and SpliceAI does not support a damaging splicing effect (max delta score 0.03).	vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai final_classification_framework
PP4	Not assessed	No phenotype-specific evidence was identified to show that the observed clinical presentation is highly specific for a POLE-related disorder caused by this variant.
PP5	Not assessed	No independent use of external pathogenic assertions was made for this variant.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the >1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. The observed allele frequency is 0, which is below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No dataset was identified showing this variant in well-phenotyped unaffected individuals at a frequency sufficient for BS2.
BS3	Not assessed	No well-established functional study was identified showing a benign effect for this exact variant.	spliceai
BS4	Not assessed	No evidence was identified that this variant fails to segregate with disease in a family.
BP1	N/A	BP1 is a missense criterion, and this variant is synonymous.	clinvar
BP2	Not assessed	No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	BP3 applies to certain in-frame variants in repetitive regions and does not apply to this synonymous substitution.	clinvar
BP4	N/A	The local POLE BP4 rule is restricted to exact missense variants represented in the León-Castillo supplementary in silico tables. This synonymous variant is not listed in those tables, and benign splicing prediction is better captured under BP7.	vcep_path_250_323_s003 vcep_path_250_323_s004 spliceai final_classification_framework
BP5	Not assessed	No alternate molecular explanation or case-level context was identified that would support BP5 for this variant.
BP6	Not assessed	No independent use of external benign assertions was made for this criterion.	clinvar
BP7	Met	This is a synonymous variant outside the canonical splice dinucleotides, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03. Available evidence does not support an effect on RNA splicing.	spliceai pvs1_variant_assessment

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