Variant classification summary

NM_001127510.3:c.6873A>T

APC · NP_001120982.1:p.(Gln2291His) · NM_001127510.3

GRCh37: chr5:112178164 A>T · GRCh38: chr5:112842467 A>T

Gene: APC Transcript: NM_001127510.3

Final call

VUS

BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Gln2291His)

gnomAD AF

0.00023172731024073616 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 supporting: p.(Gln2291His) is an APC missense change at codon 2291, outside the excluded codons 1021-1035.

Final determination: No pathogenic or benign criteria-combination rule in the APC VCEP Version 2.1 framework matches the adjudicated criteria, so the variant remains a Variant of Uncertain Significance.

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.6873A>T is a missense change producing p.(Gln2291His), not an APC null or canonical splice variant covered by PVS1.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1	Not met	Not met: p.(Gln2291His) has no documented same-amino-acid APC comparator among the VCEP's two established missense variants.	cspec
PS2	Not assessed	Not assessed: no proband-level parental testing or confirmed maternity and paternity evidence is documented.	cspec
PS3	Not assessed	Not assessed: no variant-specific validated damaging assay was available, and the APC protein-assay route is restricted to codons 959-2129 while this variant affects codon 2291.	cspec
PS4	Not assessed	Not assessed: no usable phenotype-point total, case-control enrichment estimate, or exact-variant affected-individual evidence is available for PS4.	cspec vcep_table_1_262 PMID:22703879 PMID:22855150 PMID:23429431 PMID:23788249 PMID:24033266 PMID:24310308 PMID:25356965 PMID:25479140
PM1	N/A	Not applicable: the APC VCEP marks PM1 not applicable and supplies no authoritative domain-table entry for this gene.	cspec
PM2	Not assessed	Not assessed: required gnomAD v2.1.1 non-cancer AF is unavailable; all-comers AFs are 0.000145204 and 0.000231727, above the VCEP PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP version 2.1 explicitly designates PM3 as not applicable for APC.	cspec
PM4	N/A	Not applicable: APC VCEP designates PM4 unused, and c.6873A>T causes a missense substitution without a protein-length change.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not assessed	Not assessed: zero p.Gln2291 comparator candidates were retrieved, but the comparator search recorded an HTTP 429 failure.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed-de-novo observation or de novo score is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives, informative pedigree, or countable segregating meioses are documented.	cspec
PP2	N/A	Not applicable: the APC VCEP excludes PP2 because missense variants are not a frequent disease mechanism in APC.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.00 and Pangolin scores 0.001/-0.006 do not support the APC VCEP's deleterious-splicing requirement.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP explicitly excludes PP4 because phenotype evidence is captured through its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: the APC VCEP excludes PP5, and ClinVar shows no exact-variant expert-panel classification for this variant.	cspec clinvar
BA1	Not assessed	Not assessed: the required gnomAD v2.1.1 non-cancer Popmax AF is unavailable; available all-comers grpmax FAFs are 0.00022755 and 0.00027477 versus 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: the required gnomAD v2.1.1 non-cancer Popmax AF is unavailable; available all-comers grpmax FAFs exceed the 0.00001 threshold but are not the specified source.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: available all-comers gnomAD v2.1 and v4.1 report zero homozygotes, but the VCEP-specified non-cancer homozygote dataset is unavailable.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional assay was available, and the APC protein-assay route is restricted to codons 959-2129 while this variant affects codon 2291.	cspec
BS4	Not assessed	Not assessed: no affected, variant-negative relative with an APC phenotype score is documented.	cspec
BP1	Met	Met, supporting: codon 2291 lies outside the VCEP's BP1 exception at codons 1021-1035.	cspec
BP2	Not assessed	Not assessed: no documented phase, affected-proband observation, or second (Likely) Pathogenic APC variant is available for this case.	cspec
BP3	N/A	Not applicable: APC VCEP designates BP3 unused, and p.(Gln2291His) 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 BP4 for this missense variant, p.(Gln2291His).	cspec
BP5	Not assessed	Not assessed: no documented alternate pathogenic polyposis-gene finding with the required colorectal polyposis phenotype establishes BP5.	cspec
BP6	N/A	Not applicable: the APC VCEP excludes BP6, and no exact-variant ClinVar expert-panel benign or likely-benign classification is present.	cspec clinvar
BP7	N/A	Not applicable: BP7 is restricted to synonymous or qualifying intronic variants, whereas this variant is missense, p.(Gln2291His).	cspec

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