LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_000038.6_c.3920T_A_20261029_061514
Framework: ACMG/AMP 2015
Variant classification summary

NM_000038.6:c.3920T>A

APC  · NP_000029.2:p.(Ile1307Lys)  · NM_000038.6
GRCh37: chr5:112175211 T>A  ·  GRCh38: chr5:112839514 T>A
Gene: APC Transcript: NM_000038.6
Final call
Benign
PS3 supporting BS1 strong BS2 strong BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
APC
Transcript
NM_000038.6
Protein
NP_000029.2:p.(Ile1307Lys)
gnomAD AF
0.0012391281989643367 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 Supporting: I1307K showed compromised beta-catenin-regulated transcriptional function in repeated luciferase assays.
2
BS1 Strong: the non-cancer gnomAD Popmax filtering allele frequency is 0.054599%, above the APC VCEP threshold.
3
BS2 Strong: seven non-cancer gnomAD homozygotes exceed the APC VCEP threshold of two.
4
BP1 Supporting: codon 1307 lies outside the APC VCEP missense exception at codons 1021-1035.
Final determination: Under Rule26 of the ClinGen InSiGHT APC VCEP Version 2.1 framework, at least two strong benign criteria classify the variant as Benign; BS1 Strong and BS2 Strong satisfy this rule.
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.3920T>A is a missense SNV, whereas the APC VCEP PVS1 rule applies to null variants such as nonsense, frameshift, splice, or deletion variants.
pvs1_variant_assessment vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1 Not met Not met: p.Ile1307Lys is at residue 1307, whereas the APC VCEP limits missense PS1 use to established changes at residues 1026 or 1028.
cspec vcep_apc_specifications_supplementary_material_v2
PS2 Not assessed Not assessed: no confirmed parental relationships, phenotype-point assignment, or VCEP de novo score is available for this variant.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:9724771 PMID:10938175 PMID:18343606
PS3 Met Met, Supporting: I1307K showed compromised beta-catenin-regulated transcription in at least 10 independent luciferase experiments, satisfying the VCEP protein-assay PS3 rule.
vcep_apc_specifications_supplementary_material_v2 cspec PMID:18199528
PS4 Not met Not met: verified studies showed OR 1.35 (95% CI 0.48-3.82), OR 0.21 (0.05-0.81), and OR 3.01 (0.38-23.61), without consistent significant enrichment.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:10938175 PMID:9724771 PMID:18199528 PMID:18343606
PM1 N/A Not applicable: the APC VCEP marks PM1 not applicable and identifies no approved APC missense hotspot or critical-domain route covering residue 1307.
cspec vcep_apc_specifications_supplementary_material_v2
PM2 Not met Not met: non-cancer gnomAD v2.1.1 AF is 0.201248% with 476 alleles, exceeding the APC VCEP PM2 threshold of 0.0003%.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
PM3 N/A Not applicable: the APC VCEP explicitly marks PM3 as not applicable for this autosomal-dominant condition.
cspec final_classification_framework
PM4 N/A Not applicable: the APC VCEP explicitly does not use PM4 due to limited available data, and this missense SNV causes no protein-length change.
vcep_apc_specifications_supplementary_material_v2 pvs1_variant_assessment
PM5 Not met Not met: PM5 is limited to APC residues 1026 and 1028, while p.Ile1307Lys affects residue 1307 and has no VCEP-qualified same-residue comparator.
cspec vcep_apc_specifications_supplementary_material_v2
PM6 Not assessed Not assessed: no assumed-de-novo proband record, parental-relationship information, phenotype points, or VCEP de novo score is available.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:9724771 PMID:10938175 PMID:18343606
PP1 Not assessed Not assessed: no family pedigree or informative meiosis count demonstrates cosegregation of c.3920T>A with the APC phenotype.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:9724771 PMID:10938175 PMID:18343606
PP2 N/A Not applicable: the APC VCEP marks PP2 not applicable because missense variants are not a frequent APC mutation type and most are benign, likely benign, or VUS.
cspec vcep_apc_specifications_supplementary_material_v2
PP3 Not met Not met: SpliceAI maximum delta score is 0.00, indicating no significant splice impact for this missense variant under the APC VCEP PP3 path.
cspec vcep_apc_specifications_supplementary_material_v2 spliceai
PP4 N/A Not applicable: the APC VCEP states that PP4 is already captured by PS4 and cannot provide independent evidence.
vcep_apc_specifications_supplementary_material_v2 cspec
PP5 N/A Not applicable: the APC VCEP says PP5 is not used because expert opinions require the accompanying primary evidence for independent evaluation.
vcep_apc_specifications_supplementary_material_v2 cspec
BA1 Not met Not met: non-cancer gnomAD v2.1.1 Popmax FAF is 0.054599%, below the APC VCEP BA1 threshold of 0.1%.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS1 Met Met, Strong: non-cancer gnomAD v2.1.1 Popmax FAF is 0.054599%, exceeding the APC VCEP BS1 threshold of 0.001%.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS2 Met Met, Strong: the non-cancer gnomAD v2.1.1 dataset reports 7 homozygotes, exceeding the APC VCEP requirement of at least 2.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS3 Not met Not met: I1307K showed compromised rather than wild-type-comparable beta-catenin transcriptional function in the reported protein assay.
vcep_apc_specifications_supplementary_material_v2 cspec PMID:18199528
BS4 Not assessed Not assessed: no affected noncarrier with VCEP-assigned phenotype points demonstrates non-segregation of the APC variant.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:9724771 PMID:10938175 PMID:18343606
BP1 Met Met, Supporting: p.Ile1307Lys is a missense variant at codon 1307, outside the APC VCEP BP1 exception spanning codons 1021–1035.
cspec vcep_apc_specifications_supplementary_material_v2
BP2 Not assessed Not assessed: Table 1 reports I1307K in 2 FAP patients, but establishes neither an in-trans pathogenic APC partner nor ≥3 qualifying unknown-phase observations.
cspec PMID:18199528
BP3 N/A Not applicable: the APC VCEP explicitly does not use BP3 due to limited available data, and this variant is a missense SNV rather than an in-frame indel.
vcep_apc_specifications_supplementary_material_v2 pvs1_variant_assessment
BP4 N/A Not applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI score of 0.00.
cspec vcep_apc_specifications_supplementary_material_v2
BP5 Not assessed Not assessed: the VCEP requires a qualifying alternate polyposis-gene basis, but no such second genetic diagnosis is documented.
vcep_apc_specifications_supplementary_material_v2 cspec
BP6 N/A Not applicable: the APC VCEP explicitly prohibits use of BP6 for this VCEP.
vcep_apc_specifications_supplementary_material_v2 cspec
BP7 N/A Not applicable: BP7 covers synonymous or qualifying intronic variants, whereas c.3920T>A is a missense exonic variant.
cspec vcep_apc_specifications_supplementary_material_v2
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