LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_006231.4:c.122C>T
POLE
· NP_006222.2:p.(Thr41Met)
· NM_006231.4
GRCh37: chr12:133257806 G>A
·
GRCh38: chr12:132681220 G>A
Gene:
POLE
Transcript:
NM_006231.4
Final call
VUS
PM2 moderate
BP4 supporting
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Thr41Met)
gnomAD AF
1.9825043986816347e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Moderate): rare in gnomAD v4.1, with an overall allele frequency of 1.98e-05 and no homozygotes.
2
BP4 (Supporting): REVEL 0.177 is below the <0.250 benign-supporting threshold.
3
Final: PM2_Moderate and BP4_Supporting do not combine to meet any ACMG/AMP 2015 threshold, yielding a classification of VUS.
Final determination:
Under the local POLE framework's retained ACMG/AMP 2015 final-combination rules, PM2_Moderate plus BP4_Supporting meets no pathogenic or benign category and is therefore 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: p.(Thr41Met) is a missense substitution, not a predicted null (nonsense, frameshift, or canonical splice) variant. |
pvs1_variant_assessment
pvs1_generic_framework
|
| PS1 | Not assessed | Not assessed: no pathogenic POLE variant producing the same p.(Thr41Met) change via a different nucleotide change is documented. |
clinvar
|
| PS2 | Not assessed | Not assessed: no de novo observation is documented; parental testing and trio data are absent. |
|
| PS3 | Not assessed | Not assessed: no validated variant-specific functional assay demonstrating a damaging effect was identified. |
oncokb
PMID:25741868
|
| PS4 | Not met | Not met: p.(Thr41Met) is not among the four specified variants qualifying for PS4_Supporting under the local POLE rule. |
vcep_path_250_323_s002
|
| PM1 | Not met | Not met: p.Thr41Met is not one of the specified POLE exonuclease-domain hotspot substitutions. |
vcep_path_250_323
|
| PM2 | Met | Met (Moderate): overall allele frequency is 1.98e-05 in gnomAD v4.1, below the 0.1% rarity threshold in every ancestry group. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no proband observations or second allele establish a recessive context for this variant. |
|
| PM4 | N/A | Not applicable: single-nucleotide missense substitution causes no protein-length change. |
pvs1_variant_assessment
|
| PM5 | Not assessed | Not assessed: no same-residue POLE comparator variants were available, so PM5 semantics could not be confirmed. |
pm5_candidates
|
| PM6 | Not assessed | Not assessed: no unconfirmed de novo observation is documented. |
|
| PP1 | Not assessed | Not assessed: no segregation data from affected or unaffected relatives are available. |
|
| PP2 | Not assessed | Not assessed: POLE lacks a validated gene-specific rule establishing predominantly pathogenic missense variation. |
|
| PP3 | Not met | Not met: REVEL is 0.177, below the >0.750 pathogenic-supporting threshold. |
revel
vcep_path_250_323_s003
vcep_path_250_323_s004
generic_acmg_combination_rules
|
| PP4 | Not assessed | Not assessed: no individual phenotype or clinical diagnosis data are available. |
|
| PP5 | Not met | Not met: no ClinVar expert-panel Pathogenic or Likely Pathogenic assertion exists for this exact variant. |
clinvar
|
| BA1 | Not met | Not met: highest population frequency is 0.00051 (East Asian subgroup), far below the 1% BA1 threshold. |
gnomad_v4
gnomad_v2
generic_acmg_combination_rules
|
| BS1 | Not met | Not met: maximum subgroup frequency is 0.00051 (0.05%), below the 0.3% BS1 threshold. |
gnomad_v4
gnomad_v2
generic_acmg_combination_rules
|
| BS2 | Not assessed | Not assessed: gnomAD reports zero homozygotes, and no phenotype-ascertained healthy-adult data are available. |
gnomad_v4
gnomad_v2
|
| BS3 | Not assessed | Not assessed: no validated functional assay evidence of a normal or benign effect exists for this variant. |
oncokb
PMID:25741868
|
| BS4 | Not assessed | Not assessed: no observations of affected relatives lacking the variant are documented. |
|
| BP1 | Not assessed | Not assessed: POLE-related disease is not established as primarily truncating, so the benign-missense rule cannot be applied. |
|
| BP2 | Not assessed | Not assessed: no phase-resolved data show the variant in cis with a pathogenic or in trans with a benign allele. |
|
| BP3 | N/A | Not applicable: missense substitution, not an in-frame insertion/deletion in a repetitive region. |
pvs1_variant_assessment
|
| BP4 | Met | Met (Supporting): REVEL is 0.177, below the <0.250 benign-supporting threshold. |
revel
vcep_path_250_323_s003
vcep_path_250_323_s004
generic_acmg_combination_rules
|
| BP5 | Not assessed | Not assessed: no individual-level data identify a fully explanatory alternative cause. |
|
| BP6 | Not met | Not met: no ClinVar expert-panel Benign or Likely Benign assertion exists for this exact variant. |
clinvar
|
| BP7 | N/A | Not applicable: p.(Thr41Met) is a missense, not 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.