Variant classification summary

NM_001127510.3:c.4072G>A

APC · NP_001120982.1:p.(Ala1358Thr) · NM_001127510.3

GRCh37: chr5:112175363 G>A · GRCh38: chr5:112839666 G>A

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Ala1358Thr)

gnomAD AF

0.00015861391267064936 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 strong: gnomAD v4.1 grpmax FAF 0.0001909 exceeds the APC threshold of 0.00001.

2

BP1 supporting: p.Ala1358Thr is an APC missense change at codon 1358, outside the excluded codons 1021-1035.

Final determination: APC VCEP Rule26 is satisfied by one Benign.Strong criterion (BS1) and one Benign.Supporting criterion (BP1), resulting in 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: c.4072G>A is a missense change producing p.(Ala1358Thr), not a PVS1-eligible null or canonical splice variant.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 pvs1_variant_assessment
PS1	Not met	Not met: APC VCEP examples are p.Asn1026Ser and p.Ser1028Arg, whereas this variant produces p.Ala1358Thr.	cspec vcep_apc_specifications_supplementary_material_v2
PS2	Not assessed	Not assessed: no proband-level parental testing or confirmed maternity and paternity evidence is available to calculate an APC de novo score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
PS3	Not assessed	Not assessed: no variant-specific RNA or protein assay result is available to demonstrate a damaging functional effect for p.Ala1358Thr.	cspec clinvar oncokb
PS4	Not assessed	Not assessed: exact-variant colorectal cancer reports lack the individual phenotype details required to calculate the APC VCEP PS4 phenotype-point score.	cspec clinvar
PM1	N/A	Not applicable: the governing APC VCEP explicitly designates PM1 as not applicable, with no approved domain-table entry for APC.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: gnomAD v4.1 AF 0.000158614 with allele count 256 exceeds the APC PM2 threshold of 0.000003 for counts above one.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP explicitly excludes PM3 for autosomal dominant familial adenomatous polyposis.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: APC VCEP does not use PM4, and c.4072G>A causes p.(Ala1358Thr) without a protein-length change.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not met	Not met: no useful same-residue comparator was identified for p.Ala1358Thr, while APC PM5 examples are limited to codons 1026 and 1028.	cspec pm5_candidates vcep_apc_specifications_supplementary_material_v2
PM6	Not assessed	Not assessed: no assumed-de-novo proband observation or parental testing details are available to calculate the APC PM6 score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
PP1	Not assessed	Not assessed: no affected relatives, transmitting relatives, or meioses are reported to meet the APC PP1 thresholds.	cspec vcep_apc_specifications_supplementary_material_v2
PP2	N/A	Not applicable: the governing APC VCEP explicitly designates PP2 as not applicable to APC.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: SpliceAI maximum delta 0.001 is below the 0.2 supporting threshold and does not support a deleterious splice effect.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP explicitly excludes PP4 because phenotype specificity is captured by its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: APC excludes PP5, and the exact-variant ClinVar record has zero expert-panel Pathogenic or Likely pathogenic submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.0001909 is below the APC BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met, strong: gnomAD v4.1 grpmax FAF 0.0001909 exceeds the APC BS1 threshold of 0.00001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 reports zero homozygotes, but no qualifying healthy-individual point count is available for the APC BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign RNA or protein assay with wild-type comparison and required controls is available for p.Ala1358Thr.	cspec clinvar oncokb
BS4	Not assessed	Not assessed: no affected noncarrier with an APC phenotype score is reported to satisfy the BS4 non-segregation thresholds.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
BP1	Met	Met at supporting: APC BP1 excludes only codons 1021-1035, and p.Ala1358Thr is at codon 1358.	cspec vcep_apc_specifications_supplementary_material_v2
BP2	Not assessed	Not assessed: no qualifying in-trans observation or three unknown-phase observations with different pathogenic APC variants is documented.	cspec vcep_apc_specifications_supplementary_material_v2
BP3	N/A	Not applicable: APC VCEP does not use BP3, and this missense substitution is not an in-frame indel in a repetitive region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the APC VCEP explicitly excludes missense variants from BP4, regardless of the available predictor scores.	cspec
BP5	Not assessed	Not assessed: no qualifying (Likely) Pathogenic alternate-gene variant is documented for a colorectal polyposis phenotype.	cspec
BP6	N/A	Not applicable: APC excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign classification exists.	cspec clinvar
BP7	N/A	Not applicable: p.(Ala1358Thr) is a missense consequence, whereas BP7 is restricted to synonymous or qualifying intronic variants.	cspec

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