NM_006231.4:c.889T>C

POLE · NP_006222.2:p.(Ser297Pro) · NM_006231.4

GRCh37: chr12:133253152 A>G · GRCh38: chr12:132676566 A>G

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ser297Pro)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

POLE p.(Ser297Pro) is absent from gnomAD v2.1.

The variant is also absent from gnomAD v4.1, supporting rarity, although no explicit POLE-specific population cutoff was retrieved.

SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, but no explicit computational threshold framework was retrieved to convert the available in silico data into PP3 or BP4.

No ClinVar classification has been reported for this variant.

With PM2 applied and no additional pathogenic or benign criteria established, this variant is classified as a variant of uncertain significance under the retrieved generic ACMG/AMP combination rules.

Final determination:

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	NM_006231.4:c.889T>C is a missense substitution predicted as p.(Ser297Pro) / p.(S297P), not a null variant in a gene where loss of function is being evaluated under PVS1.
PS1	Not assessed	No retrieved source established that this amino-acid change matches a previously classified pathogenic variant at the same residue with the same protein consequence.	clinvar
PS2	Not assessed	No de novo data were retrieved.
PS3	Not assessed	No well-established functional assay data were retrieved for this variant.
PS4	Not assessed	No case-control enrichment or multiple independent affected observations were retrieved.	clinvar
PM1	Not met	This residue was not identified as a statistically significant hotspot, and no critical functional domain evidence meeting PM1 was retrieved.
PM2	Met	The variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity. No explicit POLE-specific PM2 frequency cutoff was retrieved, so this is a generic ACMG rarity assessment.	gnomad_v2 gnomad_v4
PM3	Not assessed	No phase data or occurrence with another pathogenic allele were retrieved.
PM4	N/A	This is a single amino-acid substitution and does not produce a protein length change.
PM5	Not assessed	No different pathogenic missense change at codon 297 was retrieved.	clinvar
PM6	Not assessed	No assumed de novo data without parental confirmation were retrieved.
PP1	Not assessed	No segregation data were retrieved.
PP2	Not assessed	No retrieved gene-level evidence established that missense variation is a predominant disease mechanism suitable for PP2 application.
PP3	Not assessed	REVEL is 0.774 and SpliceAI maximum delta score is 0.00, but no explicit computational threshold framework applicable to this case was retrieved to convert these values into PP3.	spliceai
PP4	Not assessed	No phenotype-specific evidence for a highly specific POLE-associated presentation was provided.
PP5	Not assessed	No reputable external pathogenic classification was retrieved.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet a stand-alone benign population frequency criterion.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet a benign strong population frequency criterion.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observations in healthy adult individuals inconsistent with disease penetrance were retrieved.
BS3	Not assessed	No well-established functional evidence demonstrating no damaging effect was retrieved.
BS4	Not assessed	No lack-of-segregation data were retrieved.
BP1	Not assessed	No retrieved gene-level evidence supported BP1 for this missense variant.
BP2	Not assessed	No phase data with another pathogenic variant were retrieved.
BP3	Not assessed	No evidence was retrieved that the variant lies in a repetitive region without known function.
BP4	Not met	Benign computational evidence was not established. SpliceAI shows a maximum delta score of 0.00, but REVEL is 0.774 and no retrieved framework supported an overall benign in silico interpretation.	spliceai
BP5	Not assessed	No alternate molecular explanation accounting for the phenotype was retrieved.
BP6	Not assessed	No reputable benign classification was retrieved.	clinvar
BP7	N/A	BP7 is for synonymous or certain intronic variants without predicted splice impact; this variant is missense.	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.