Variant classification summary

NM_006231.4:c.4477G>C

POLE · NP_006222.2:p.(Ala1493Pro) · NM_006231.4

GRCh37: chr12:133219884 C>G · GRCh38: chr12:132643298 C>G

Gene: POLE Transcript: NM_006231.4

Final call

Likely Benign

PM2 supporting BP4 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ala1493Pro)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

2

Likely Benign: BP4 supporting reflects a REVEL score of 0.147 below 0.250.

Final determination: Under the local POLE framework's ACMG/AMP combination rules, two supporting benign criteria, PM2 and BP4, yield a Likely Benign classification.

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	Not applicable: c.4477G>C is a missense substitution producing p.(Ala1493Pro), not one of the null-variant types named by PVS1.
PS1	Not assessed	Not assessed: no previously established pathogenic variant producing the same Ala1493Pro amino-acid change was identified in the reviewed sources.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, family-history assessment, parental genotypes, or confirmed maternity and paternity are available.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or result demonstrating a damaging effect on POLE p.Ala1493Pro is available.
PS4	Not assessed	PS4 could not be assessed because its agent did not produce valid output.
PM1	Not met	Not met: Ala1493Pro is absent from all three POLE PM1 substitution lists, including the five established hotspots and ten recurrent exonuclease-domain variants.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, consistent with allele frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented pathogenic second allele, parental testing, phase result, affected proband, or inheritance mode establishes a recessive in-trans observation.
PM4	N/A	Not applicable: p.(Ala1493Pro) is a missense substitution with no protein-length change, whereas PM4 requires an in-frame indel or stop-loss variant.
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at the same Ala1493 residue was identified in the reviewed evidence.	pm5_candidates vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM6	Not assessed	Not assessed: no parental genotypes or parentage information establish that the variant is assumed de novo.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, segregation results, or phenotype-matched family members are documented.
PP2	Not assessed	Not assessed: the reviewed evidence does not establish both a low benign-missense rate and a common missense disease mechanism for POLE.
PP3	Not met	Not met: REVEL 0.147 is below the generic missense PP3 threshold of >0.750 after no exact entry was found in either governing supplementary table.	vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004 revel
PP4	Not assessed	PP4 could not be assessed because its agent did not produce valid output.
PP5	Not assessed	PP5 could not be assessed because its agent did not produce valid output.
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the >=0.05 stand-alone benign frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 showed no variant observations, below the generic BS1 allele-frequency threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier, zygosity, age, or penetrance observation was documented for this variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or result showing no damaging effect on POLE p.Ala1493Pro is available.
BS4	Not assessed	Not assessed: no affected relatives with documented phenotypes and variant-negative genotypes are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the reviewed evidence does not establish that POLE disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic variant or phase result is documented to establish the required cis or trans relationship for BP2.
BP3	N/A	Not applicable: c.4477G>C is a missense substitution, not an in-frame deletion or insertion required for BP3.
BP4	Met	Met at supporting: REVEL 0.147 is below the generic missense BP4 threshold of <0.250 after no exact entry was found in either governing supplementary table.	vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004 revel
BP5	Not assessed	BP5 could not be assessed because its agent did not produce valid output.
BP6	Not assessed	BP6 could not be assessed because its agent did not produce valid output.
BP7	N/A	Not applicable: c.4477G>C is a missense variant producing p.Ala1493Pro, not a synonymous substitution required for BP7.	generic_acmg_combination_rules

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