LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_006231.4:c.5066C>T
POLE
· NP_006222.2:p.(Thr1689Ile)
· NM_006231.4
GRCh37: chr12:133218870 G>A
·
GRCh38: chr12:132642284 G>A
Gene:
POLE
Transcript:
NM_006231.4
Final call
VUS
PM2 supporting
BP4 supporting
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Thr1689Ile)
gnomAD AF
0.0 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): absent from gnomAD v2.1, v4.1 (0 of 1,608,632 alleles), and gnomAD-Canada v1.0.
2
BP4 (Supporting): REVEL score 0.178 is below the 0.250 benign threshold.
3
VUS: PM2_Supporting plus BP4_Supporting meets no pathogenic or benign combination rule under the local POLE framework.
Final determination:
Under the local POLE framework's retained ACMG/AMP 2015 final-combination rules, one pathogenic supporting criterion plus one benign supporting criterion is a conflicting, non-qualifying combination and is classified as 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 | Not met | Not met: this is a missense substitution, p.(Thr1689Ile), not a predicted null (nonsense, frameshift, or splice-site) variant. |
clinvar
pvs1_variant_assessment
pvs1_generic_framework
|
| PS1 | Not assessed | Not assessed: no verified pathogenic variant producing the same p.Thr1689Ile change was available; ClinVar's sole submission is uncertain significance. |
clinvar
|
| PS2 | Not assessed | Not assessed: no de novo assertion, parental genotypes, or maternity/paternity confirmation was documented. |
|
| PS3 | Not assessed | Not assessed: no variant-specific validated functional assay result for p.Thr1689Ile was available. |
PMID:25741868
oncokb
|
| PS4 | Not met | Not met: p.Thr1689Ile is not among the four exonuclease-domain variants the POLE framework qualifies for PS4, and no COSMIC record exists. |
final_classification_framework
vcep_path_250_323_s002
|
| PM1 | Not met | Not met: p.Thr1689Ile is not a listed exonuclease-domain hotspot, and no statistically significant hotspot at Thr1689 was reported. |
final_classification_framework
vcep_path_250_323
|
| PM2 | Met | Met (Supporting): absent from gnomAD v2.1 and v4.1 (allele count 0 of 1,608,632, AF 0.0) and from gnomAD-Canada v1.0. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no confirmed in-trans pathogenic comparator, phase information, or biallelic disease evidence was available. |
PMID:25741868
|
| PM4 | Not met | Not met: a single amino-acid substitution with no in-frame insertion/deletion or protein-length alteration. |
clinvar
|
| PM5 | Not assessed | Not assessed: no verified same-residue comparator variant at Thr1689 was identified. |
pm5_candidates
|
| PM6 | Not assessed | Not assessed: no de novo observation with confirmed maternity and paternity was documented. |
|
| PP1 | Not assessed | Not assessed: no segregation data, informative meioses, or relative genotype information was available. |
|
| PP2 | Not assessed | Not assessed: no POLE-specific data showing pathogenic missense predominates with a low benign missense rate. |
final_classification_framework
oncokb
|
| PP3 | Not met | Not met: REVEL score 0.178 is below the PP3 threshold and instead meets BP4. |
vcep_path_250_323_s003
vcep_path_250_323_s004
revel
generic_acmg_combination_rules
|
| PP4 | Not assessed | Not assessed: no proband or tumor phenotype indicating a POLE-related disorder was supplied. |
|
| PP5 | Not met | Not met: ClinVar has only one uncertain-significance submission and no expert-panel pathogenic assertion for this exact variant. |
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 allele frequency is 0.00000% versus the >5% stand-alone benign threshold. |
gnomad_v4
|
| BS1 | Not met | Not met: absent from all gnomAD datasets, with no allele frequency above the maximum credible population frequency. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS2 | Not met | Not met: no healthy adult carriers documented; gnomAD reports 0 homozygotes. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS3 | Not assessed | Not assessed: no validated benign functional assay evidence for p.Thr1689Ile was available. |
PMID:25741868
oncokb
|
| BS4 | Not assessed | Not assessed: no unaffected relatives tested or informative non-segregation analysis documented. |
|
| BP1 | Not assessed | Not assessed: no POLE-specific rule establishing that missense variants are generally tolerated. |
final_classification_framework
vcep_path_250_323
|
| BP2 | Not assessed | Not assessed: no in-trans observation with a pathogenic variant or phase information was available. |
PMID:25741868
|
| BP3 | Not met | Not met: missense substitution produces no in-frame protein-length change. |
clinvar
|
| BP4 | Met | Met (Supporting): REVEL score 0.178 is below the 0.250 BP4 threshold. |
vcep_path_250_323_s003
vcep_path_250_323_s004
revel
generic_acmg_combination_rules
|
| BP5 | Not assessed | Not assessed: no individual phenotype or alternate molecular diagnosis was supplied. |
|
| BP6 | Not met | Not met: no ClinVar expert-panel benign assertion exists; the sole submission is uncertain significance. |
clinvar
|
| BP7 | N/A | Not applicable: the variant is a missense substitution, 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.