NM_006231.4:c.4744C>T

POLE · NP_006222.2:p.(Pro1582Ser) · NM_006231.4

GRCh37: chr12:133219300 G>A · GRCh38: chr12:132642714 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

BS1 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Pro1582Ser)

gnomAD AF

0.0001983214567702607 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BS1 (Supporting): gnomAD South Asian allele frequency 0.338-0.395% exceeds the 0.3% benign-frequency threshold but remains below the 1% BA1 cutoff.

Overall classification VUS: with BS1 as the only met criterion, no pathogenic criterion applies and the benign combinations (one strong plus one supporting, or two supporting) are not satisfied.

Final determination: Under the local custom POLE gene framework (León-Castillo et al. 2020), which retains standard ACMG/AMP 2015 final-combination logic, only BS1 (supporting) is met; BA1 is not met and the benign combinations (2 Strong benign; 1 Strong benign + 1 Supporting benign; >=2 Supporting benign) are unsatisfied with only one supporting benign criterion, while no pathogenic combination is approached, so 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	Not met	Not met: this missense change (p.Pro1582Ser) is not a null variant such as nonsense, frameshift, or splice-site disruption.	pvs1_variant_assessment pvs1_generic_framework final_classification_framework
PS1	Not assessed	Not assessed: no previously established pathogenic variant producing the same amino acid change (p.Pro1582Ser) via a different nucleotide change was available.	pm5_candidates clinvar
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo occurrence was available to support this criterion.	PMID:25741868 clinvar PMID:25394175
PS3	Not met	Not met: no functional assay evidence exists for this variant; OncoKB lists it as having unknown oncogenic effect.
PS4	Not met	Not met: only one somatic occurrence in COSMIC, well below the required recurrent count of at least 10, with no case-control enrichment.	final_classification_framework vcep_path_250_323_s002 clinvar
PM1	Not met	Not met: residue 1582 lies outside the exonuclease-domain hotspot region (~amino acids 268-471) and is not a statistically significant hotspot.	final_classification_framework vcep_path_250_323 vcep_path_250_323_s002
PM2	Not met	Not met: the highest population frequency is 0.338% (gnomAD South Asian), above the 0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no data show the variant in trans with a pathogenic POLE variant.
PM4	Not met	Not met: p.Pro1582Ser is a single amino-acid substitution with no protein-length alteration.	pvs1_variant_assessment final_classification_framework
PM5	Not assessed	Not assessed: no different pathogenic missense change at codon 1582 was available as a comparator.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no evidence indicates the variant arose de novo.	PMID:25741868 clinvar PMID:25394175
PP1	Not assessed	Not assessed: no co-segregation data in affected family members were available.	PMID:25741868 clinvar PMID:25394175
PP2	Not assessed	Not assessed: POLE's rate of benign missense variation could not be evaluated because no gene-level constraint metric was available.	PMID:25741868 final_classification_framework
PP3	Not met	Not met: REVEL score 0.564 is below the ≥0.773 supporting threshold, and SpliceAI predicts no splice impact.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel spliceai
PP4	Not assessed	Not assessed: no phenotype or phenotype-to-genotype specificity evidence was provided.	final_classification_framework
PP5	Not met	Not met: ClinVar holds no expert-panel pathogenic assertion for this variant, only single-laboratory benign, likely benign, and VUS submissions.	clinvar
BA1	Not met	Not met: the highest population frequency is 0.395% (gnomAD South Asian), below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Met	Met (supporting): gnomAD South Asian frequency of 0.338-0.395% exceeds the 0.3% BS1 threshold while staying below the 1% BA1 cutoff.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: homozygotes exist in gnomAD, but phenotype and penetrance data are lacking to judge this allele benign.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: no functional assay evidence of normal function exists for this variant.
BS4	Not assessed	Not assessed: no documented lack of segregation in affected relatives was available.	PMID:25741868 clinvar PMID:25394175
BP1	Not met	Not met: missense variants are an established disease mechanism in POLE, so this criterion for truncation-only genes does not apply.	PMID:25741868 final_classification_framework clinvar
BP2	Not assessed	Not assessed: no allelic observation with established phase (in trans or in cis) was available.
BP3	Not met	Not met: this is a missense substitution, not an in-frame insertion or deletion.	pvs1_variant_assessment final_classification_framework
BP4	Not met	Not met: REVEL score 0.564 is above the ≤0.290 benign threshold, and one benign splice prediction alone is insufficient.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate molecular basis for disease in the tested individual was provided.
BP6	Not met	Not met: ClinVar holds no expert-panel benign or likely benign assertion for this variant.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant.	gnomad_canada

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