Variant classification summary

NM_006231.4:c.4952+9A>G

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133219083 T>C · GRCh38: chr12:132642497 T>C

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.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The POLE c.4952+9A>G (p.?) variant has not been identified in the León-Castillo endometrial carcinoma recurrence table and has been reported in ClinVar as Likely benign by one clinical laboratory.

2

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07), which supports rarity but does not establish pathogenic enrichment.

3

SpliceAI predicts low splice impact for NM_006231.4 with a maximum delta score of 0.07, arguing against a clinically meaningful splicing effect.

Final determination: Under the León-Castillo et al. 2020 custom POLE framework, the combination of one supporting pathogenic criterion and one supporting benign criterion does not meet thresholds for either a pathogenic/likely pathogenic or benign/likely benign classification; therefore, the variant is classified as a Variant of 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	Although POLE is flagged as eligible for generic PVS1 consideration at the gene level, this variant is an intronic +9 change and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice-site variants. PVS1 is therefore not applied.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change causing the same amino acid substitution. This intronic variant has no defined amino acid substitution, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo data with verified maternity and paternity were identified for this variant.
PS3	Not assessed	No published functional assay demonstrating an abnormal effect of this specific intronic variant was identified.
PS4	Not met	The local POLE framework limits PS4 to exact recurrent exonuclease-domain missense variants in the established pathogenic set with combined COSMIC and TCGA endometrial carcinoma counts of at least 10. This intronic variant is not listed in the recurrence table, and no germline case-control or multiple unrelated affected-proband evidence was identified.	final_classification_framework vcep_path_250_323_s002 clinvar
PM1	N/A	The local POLE PM1 framework is restricted to exact exonuclease-domain hotspot or recurrent missense substitutions highlighted by León-Castillo et al. This intronic +9 variant is not a missense exonuclease-domain hotspot and is not listed in the recurrence table, so PM1 is not applicable.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM2	Met	This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1613298 alleles; AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals), which is below the project's PM2 threshold of 0.1% and supports rarity in the general population.	gnomad_v2 gnomad_v4
PM3	Not assessed	No phase data or recessive case evidence relevant to PM3 were identified.
PM4	Not assessed	This variant is intronic and does not directly demonstrate a protein length change. No RNA evidence was identified to show in-frame exon loss or other protein-length alteration.
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This intronic variant has no amino acid substitution, so PM5 is not applicable.
PM6	Not assessed	No assumed de novo evidence without full parental confirmation was identified.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is a missense-based criterion and does not apply to this intronic variant.
PP3	Not met	Available computational evidence does not support a damaging splicing effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, and no REVEL or BayesDel score is available for this intronic variant.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified to show that the clinical presentation is highly specific for a POLE-related disorder caused by this variant.
PP5	Not assessed	No reputable-source pathogenic classification was used as stand-alone evidence for this variant.
BA1	Not met	This variant does not meet the BA1 population threshold. Its gnomAD v4.1 allele frequency is 6.20e-07 overall and 1.10e-05 in the highest-frequency population, both well below the project's BA1 threshold of 1%.	gnomad_v4
BS1	Not met	This variant does not meet the BS1 population threshold. Its highest observed gnomAD v4.1 population frequency is 1.10e-05, which is below the project's BS1 threshold of 0.3%.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a level sufficient for BS2.
BS3	Not assessed	No published functional study demonstrating a normal effect of this specific variant was identified.
BS4	Not assessed	No segregation data were identified showing lack of segregation with disease.
BP1	N/A	BP1 is a missense-based criterion and does not apply to this intronic variant.
BP2	Not assessed	No phase information was identified to assess BP2.
BP3	Not assessed	This criterion was not assessed because the variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Met	Computational splicing prediction supports no meaningful splice effect. SpliceAI for NM_006231.4 shows DS_AG 0.00, DS_AL 0.01, DS_DG 0.07, and DS_DL 0.00, with a maximum delta score of 0.07, which is below commonly used concern thresholds for splice disruption.	spliceai
BP5	Not assessed	No alternate molecular explanation sufficient to account for the phenotype independently of this variant was identified.
BP6	Not assessed	Although ClinVar contains a Likely benign submission for this variant, a reputable-source benign assertion was not used as stand-alone evidence.	clinvar
BP7	Not assessed	This intronic +9 variant has low predicted splice impact by SpliceAI, but no additional conservation-based or framework-specific BP7 assessment was available to support formal application of BP7.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.