Variant classification summary

NM_006231.4:c.2810A>G

POLE · NP_006222.2:p.(Tyr937Cys) · NM_006231.4

GRCh37: chr12:133238167 T>C · GRCh38: chr12:132661581 T>C

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Tyr937Cys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 Supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

2

VUS: no pathogenic or benign criterion is met to satisfy another combination rule.

Final determination: Under the local POLE framework's ACMG/AMP combination rules, a single Supporting pathogenic criterion does not reach a pathogenic or likely pathogenic threshold, and no benign rule is met, resulting in VUS.

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.2810A>G is a missense substitution producing p.(Tyr937Cys), not one of the null-variant types specified for PVS1.	pvs1_variant_assessment
PS1	Not assessed	Not assessed: no previously established pathogenic POLE Tyr937 substitution was identified, but a comprehensive same-amino-acid comparator review remains unavailable.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PS2	Not assessed	Not assessed: no documented proband disease, confirmed maternity and paternity, or family-history status is available for this variant.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay was identified, and OncoKB reports no variant-specific reviewed functional evidence.	oncokb
PS4	Not assessed	PS4 could not be assessed because its agent did not produce valid output.
PM1	Not met	Not met: p.Tyr937Cys is absent from all three authoritative PM1 substitution lists, and vcep_materials.json provides no additional POLE domain table.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the generic PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, pathogenic-in-trans, inheritance-mode, or parental/offspring phase evidence is documented.
PM4	N/A	Not applicable: p.(Tyr937Cys) is a missense substitution with no protein-length change, whereas PM4 requires an in-frame indel or stop-loss variant.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no pathogenic alternate missense change at Tyr937 was identified, but comprehensive same-residue comparator coverage is unavailable.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM6	Not assessed	Not assessed: neither a documented affected proband nor evidence supporting assumed de novo origin without parental confirmation is available.
PP1	Not assessed	Not assessed: no affected relatives, variant genotypes, phenotype concordance, or informative meioses are documented for co-segregation.
PP2	Not assessed	Not assessed: the case lacks validated gene-level evidence for both low benign missense variation and a common POLE missense disease mechanism.
PP3	Not assessed	Not assessed: the POLE PP3 rule requires an exact Supplementary Table S2/S3 entry, but p.Y937C was absent from both governing tables despite REVEL 0.709.	revel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
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 is absent from gnomAD v2.1 and v4.1, rather than having an allele frequency >=0.05 required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observations, not the >=0.01 allele frequency used for generic BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no reliable observation of this variant in a healthy adult individual is available for the required inheritance and penetrance context.
BS3	Not assessed	Not assessed: no validated variant-specific assay demonstrated preserved protein function or splicing for p.Tyr937Cys.	oncokb
BS4	Not assessed	Not assessed: no tested affected relatives or genotype-phenotype discordance is documented to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: no validated gene-level evidence shows that POLE disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no pathogenic-in-trans or pathogenic-in-cis observation, inheritance mode, or phase result is documented.
BP3	N/A	Not applicable: c.2810A>G is a missense substitution, not the in-frame deletion or insertion required for BP3 in a repetitive region.	pvs1_variant_assessment
BP4	Not assessed	Not assessed: the POLE BP4 rule requires an exact Supplementary Table S2/S3 entry, but p.Y937C was absent from both governing tables despite REVEL 0.709.	revel spliceai vcep_path_250_323_s003 vcep_path_250_323_s004
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.2810A>G is missense and produces p.Tyr937Cys, whereas BP7 requires a synonymous variant.

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.