LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_006231.4_c.1231G_T_20261105_101739
Framework: ACMG/AMP 2015 with custom gene-specific criterion specifications
Variant classification summary

NM_006231.4:c.1231G>T

POLE  · NP_006222.2:p.(Val411Leu)  · NM_006231.4
GRCh37: chr12:133250289 C>A  ·  GRCh38: chr12:132673703 C>A
Gene: POLE Transcript: NM_006231.4
Final call
Pathogenic
PS1 strong PS3 supporting PS4 supporting PM1 strong PM2 supporting PM6 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLE
Transcript
NM_006231.4
Protein
NP_006222.2:p.(Val411Leu)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 Strong is met by an alternate nucleotide change producing the same p.Val411Leu substitution.
2
Pathogenic: PM1 Strong is met because p.V411L is an established POLE exonuclease-domain hotspot with 114 tumor cases.
3
Pathogenic: PS3 Supporting is met by reduced human POLE V411L exonuclease activity and increased mutation frequency.
4
Pathogenic: PS4 Supporting is met by 114 recurrent COSMIC and TCGA endometrial carcinoma cases.
5
Pathogenic: PM2 Supporting is met because the variant is absent from available gnomAD datasets.
6
Pathogenic: PM6 Supporting is met by maternal absence with unavailable paternal testing, supporting assumed de novo status.
Final determination: Under the local POLE framework, two Strong pathogenic criteria satisfy the Pathogenic combination rule, and no benign rule is satisfied.
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.1231G>T is a missense variant producing p.Val411Leu, not one of the governing rule's named null-variant classes.
pvs1_variant_assessment
PS1 Met Met, strong: NM_006231.3:c.1231G>C produces the same established pathogenic p.Val411Leu change as the queried c.1231G>T variant.
vcep_path_250_323 PMID:27573199 spliceai
PS2 Not met Not met: the mother tested negative but the father was unavailable, so both maternity and paternity were not confirmed as required for PS2.
PMID:27573199
PS3 Met Met at supporting strength: human POLE V411L showed reduced exonuclease activity and increased lacZ mutation frequency versus wild type, but yeast results were discordant.
PMID:25228659 PMID:29352080
PS4 Met Met at Supporting: V411L appears in 101 COSMIC and 13 TCGA endometrial cancers, for 114 cases, satisfying the POLE framework's combined-count threshold of >=10.
vcep_path_250_323_s002 vcep_path_250_323 PMID:23636398 PMID:27573199
PM1 Met Met, strong: the POLE framework names p.V411L as an established exonuclease-domain hotspot, with 114 total COSMIC/TCGA endometrial carcinoma cases.
vcep_path_250_323 vcep_path_250_323_s002
PM2 Met Met at Supporting: the variant was absent from gnomAD v2.1, v4.1, and available non-cancer subsets, consistent with the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: one heterozygous proband was reported, but no pathogenic variant in trans or parental phase was established for a recessive disorder.
PMID:27573199
PM4 N/A Not applicable: p.Val411Leu is a missense substitution with no in-frame insertion, deletion, or stop-loss protein length change.
pvs1_variant_assessment
PM5 Not assessed Not assessed: no different pathogenic missense change at Val411 was identified; the known c.1231G>C change produces the same p.Val411Leu substitution.
pm5_candidates PMID:27573199
PM6 Met Met: the variant was absent in the mother and the father was unavailable, supporting assumed de novo status without complete parental confirmation.
PMID:27573199
PP1 Not assessed Not assessed: no multiple affected family members or cosegregation meioses were reported.
PP2 Not assessed Not assessed: the required paired evidence for low benign missense variation and a common POLE missense disease mechanism is unavailable.
PP3 Not met Not met: generic missense fallback places REVEL 0.457 in the 0.250–0.750 gray zone, and neither governing in-silico table contains this variant.
vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules revel
PP4 Not assessed Not assessed: the current patient's phenotype and family history are not sufficiently documented to judge specificity for a single-gene disease.
PP5 Not met Not met: ClinVar lists the exact variant as Uncertain significance from two clinical laboratories, with no expert-panel pathogenic classification.
clinvar
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, so no allele frequency reaches the >=0.05 BA1 threshold.
gnomad_v2 gnomad_v4 clinvar
BS1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, providing no frequency above the generic >=0.01 BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no documented healthy adult carrying the variant in the required zygosity was available for the BS2 criterion.
gnomad_v2 gnomad_v4
BS3 Not met Not met: human assays showed reduced exonuclease activity and increased mutation frequency versus wild type, so normal POLE function was not demonstrated.
PMID:25228659 PMID:29352080
BS4 Not assessed Not assessed: no affected family member was reported to lack the variant, and the tested mother was healthy.
BP1 Not assessed Not assessed: no evidence establishes that POLE disease is caused primarily by truncating rather than missense variants.
BP2 Not assessed Not assessed: the report documents one heterozygous variant but provides no confirmed pathogenic variant in trans or cis-phase result.
PMID:27573199
BP3 N/A Not applicable: p.Val411Leu is a missense substitution, not an in-frame deletion or insertion requiring repeat-region assessment.
pvs1_variant_assessment
BP4 Not met Not met: generic missense fallback places REVEL 0.457 in the 0.250–0.750 gray zone, so it does not reach the BP4 threshold.
vcep_path_250_323 vcep_path_250_323_s003 vcep_path_250_323_s004 generic_acmg_combination_rules revel
BP5 Not assessed Not assessed: no current-patient alternate molecular basis for disease is documented in the available evidence.
BP6 Not met Not met: ClinVar has only two ordinary Uncertain significance submissions and no exact-variant expert-panel benign classification.
clinvar
BP7 N/A Not applicable: c.1231G>T is a missense change encoding p.Val411Leu, not the synonymous variant required for BP7.
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