LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-02
Case ID: NM_001127510.3_c.3245C_G_20261002_201336
Framework: ACMG/AMP 2015
Variant classification summary

NM_001127510.3:c.3245C>G

APC  · NP_001120982.1:p.(Thr1082Ser)  · NM_001127510.3
GRCh37: chr5:112174536 C>G  ·  GRCh38: chr5:112838839 C>G
Gene: APC Transcript: NM_001127510.3
Final call
Likely Benign
BS1 strong BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
APC
Transcript
NM_001127510.3
Protein
NP_001120982.1:p.(Thr1082Ser)
gnomAD AF
6.877144460924808e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign driver: BS1 (strong) - gnomAD v2.1.1 non-cancer popmax filtering AF 0.0039% exceeds the APC VCEP threshold of 0.001%.
2
Likely Benign: BP1 (supporting) - missense change at residue 1082 sits outside the VCEP-excepted beta-catenin repeat codons 1021-1035.
3
Likely Benign: APC VCEP Rule26 is met by one Benign-Strong criterion, while no pathogenic combination rule is satisfied.
Final determination: Rule26 of the APC VCEP v2.1 criteria-combination ruleset: a single Benign-Strong criterion (BS1) is sufficient to infer Likely Benign.
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.Thr1082Ser is a missense substitution, not the null or canonical splice variant the APC VCEP PVS1 decision tree covers.
cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 vcep_apc_specifications_supplementary_material_v2 PMID:25142776
PS1 Not met Not met: no established pathogenic variant carries the same p.Thr1082Ser change; APC's only Likely Pathogenic missense variants are p.Asn1026Ser and p.Ser1028Arg.
cspec clinvar PMID:25142776 vcep_apc_specifications_supplementary_material_v2
PS2 Not assessed Not assessed: no proband with confirmed parentage or documented de novo occurrence, so no de novo score could be counted against the VCEP >=4/2-3.5/1-1.5 thresholds.
cspec vcep_table_1_262 PMID:25142776
PS3 Not assessed Not assessed: no RNA or protein functional assay has been reported for APC p.(Thr1082Ser), so the APC VCEP PS3 requirements cannot be evaluated.
cspec clinvar oncokb PMID:25142776 PMID:25741868 PMID:28492532
PS4 Not met Not met: 0 phenotype points assignable (no polyposis phenotype documented) against the >=1 phenotype point required for PS4_Supporting.
cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2 PMID:25142776 PMID:25452455 PMID:25645574 PMID:25741868
PM1 N/A Not applicable: the APC VCEP specifies PM1 as not applicable for this gene, with no approved APC critical-domain table to test residue 1082 against.
cspec vcep_apc_specifications_supplementary_material_v2
PM2 Not met Not met: non-cancer exome AF 0.00466% (11 alleles) exceeds the VCEP PM2 threshold of 0.0003% for allele count greater than 1.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the APC VCEP v2.1 excludes PM3 because FAP is autosomal dominant, so recessive trans/compound-heterozygote logic does not apply.
cspec vcep_apc_specifications_supplementary_material_v2
PM4 N/A Not applicable: the APC VCEP marks PM4 not used, and p.Thr1082Ser changes one amino acid with no protein length change.
cspec vcep_apc_specifications_supplementary_material_v2
PM5 Not met Not met: residue 1082 has no pathogenic alternate missense; the APC VCEP restricts PM5 to residues 1026 and 1028.
cspec pm5_candidates clinvar PMID:25142776 vcep_apc_specifications_supplementary_material_v2
PM6 Not assessed Not assessed: no de novo occurrence, even with unconfirmed parentage, is reported, so no VCEP PM6 de novo score (0.5-3.5) can be assigned.
cspec vcep_table_1_262 PMID:25142776
PP1 Not assessed Not assessed: no pedigree or meiosis data are reported, so co-segregation cannot be counted against the VCEP >=7/5-6/3-4 meiosis thresholds.
cspec vcep_apc_specifications_supplementary_material_v2 clinvar PMID:25142776
PP2 N/A Not applicable: the APC VCEP disables PP2 because truncating, not missense, variants are the primary APC disease mechanism.
cspec vcep_apc_specifications_supplementary_material_v2
PP3 Not met Not met: for APC missense variants PP3 uses splice predictors, and SpliceAI max delta 0.001 is far below the 0.2 supporting cutoff.
cspec spliceai revel bayesdel
PP4 N/A Not applicable: the APC VCEP v2.1 designates PP4 Not Applicable, its phenotype-specificity content being already captured by the gene-specific PS4 specifications.
cspec vcep_apc_specifications_supplementary_material_v2
PP5 N/A Not applicable: the APC VCEP v2.1 lists PP5 as not for use, and VCV000181799 has 0 expert-panel submissions to trigger it.
cspec clinvar vcep_apc_specifications_supplementary_material_v2
BA1 Not met Not met: highest popmax filtering AF 0.0039% (gnomAD v2.1 non-cancer) versus the VCEP BA1 stand-alone threshold of 0.1%.
cspec gnomad_v2 gnomad_v4
BS1 Met Met (strong): popmax filtering AF 0.0039% in gnomAD v2.1 non-cancer exceeds the VCEP BS1 threshold of 0.001%.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: zero homozygotes across every gnomAD dataset, and the VCEP bars counting gnomAD heterozygous carriers as healthy individuals.
cspec gnomad_v2 PMID:25142776
BS3 Not assessed Not assessed: no protein assay showing retained beta-catenin-regulated transcription has been reported for APC p.(Thr1082Ser), so the APC VCEP BS3 protein-assay branch is unevaluable.
cspec clinvar oncokb PMID:25142776 PMID:25741868 PMID:28492532
BS4 Not assessed Not assessed: no genotyped affected relative without the variant is reported, so no phenotype-point deficit can be scored for VCEP BS4.
cspec vcep_table_1_262 clinvar PMID:25142776
BP1 Met Met (supporting): p.Thr1082Ser is a missense change at residue 1082, outside the beta-catenin repeat codons 1021-1035 that the APC VCEP excepts.
cspec vcep_apc_specifications_supplementary_material_v2
BP2 Not met Not met: no source reports c.3245C>G in trans with a pathogenic APC variant, and none of the required >=3 unknown-phase co-occurrences exist.
cspec PMID:25142776 clinvar
BP3 N/A Not applicable: the APC VCEP marks BP3 not used, and p.Thr1082Ser is a missense change, not an in-frame indel in a repeat region.
cspec vcep_apc_specifications_supplementary_material_v2
BP4 N/A Not applicable: the APC VCEP restricts BP4 to synonymous or intronic variants, and this is a missense change (p.Thr1082Ser).
cspec
BP5 Not met Not met: no (likely) pathogenic variant in another adenomatous polyposis gene is documented, so the alternate-molecular-basis condition for BP5_Supporting is absent.
cspec vcep_apc_specifications_supplementary_material_v2
BP6 N/A Not applicable: the APC VCEP v2.1 lists BP6 as not for use, and VCV000181799 has 0 expert-panel submissions to trigger it.
cspec clinvar vcep_apc_specifications_supplementary_material_v2
BP7 N/A Not applicable: BP7 applies only to synonymous or intronic variants, and this variant is a missense substitution (p.Thr1082Ser).
cspec
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