Variant classification summary

NM_001127510.3:c.2204C>T

APC · NP_001120982.1:p.(Ala735Val) · NM_001127510.3

GRCh37: chr5:112173495 C>T · GRCh38: chr5:112837798 C>T

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting BP2 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Ala735Val)

gnomAD AF

7.125384460961568e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 (strong) is met because the non-cancer gnomAD Popmax FAF exceeds the APC VCEP threshold.

2

Likely Benign: BP1 (supporting) is met because codon 735 lies outside the APC VCEP missense exception at codons 1021-1035.

3

Likely Benign: BP2 (supporting) is met because the variant was observed in trans with pathogenic APC p.Arg332Ter.

Final determination: Under the APC VCEP Version 2.1 framework, one strong benign criterion satisfies the Likely Benign rule, and at least two supporting benign criteria independently satisfy the two-supporting-evidence rule; no pathogenic rule is met.

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.2204C>T is a missense SNV producing p.Ala735Val, whereas the VCEP PVS1 rule applies only to defined null-variant classes.	pvs1_variant_assessment vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 PMID:23159591
PS1	N/A	Not applicable: APC VCEP missense PS1 is restricted to residues 1026 and 1028, whereas this variant changes residue 735.	cspec vcep_apc_specifications_supplementary_material_v2
PS2	Not assessed	Not assessed: one reported case lacks confirmed maternity, paternity, parental phenotype, and a qualifying de novo observation.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23159591
PS3	Not assessed	Not assessed: no variant-specific RNA or protein functional assay was available to satisfy the APC VCEP PS3 evidence pathways.	cspec vcep_apc_specifications_supplementary_material_v2
PS4	Not assessed	Not assessed: the exact variant occurred in 1 of 1591 cases, but no Table 1 phenotype points can be assigned from the available report.	vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23159591
PM1	N/A	Not applicable: APC VCEP identifies no established pathogenic missense hotspot or approved critical-domain entry covering residue 735.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: non-cancer gnomAD v2.1 exome AF is 0.00594% with allele count 14, 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 excludes PM3 because familial adenomatous polyposis has autosomal dominant inheritance.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: the APC VCEP states PM4 is not used, and this missense substitution causes no protein-length change.	pvs1_variant_assessment vcep_apc_specifications_supplementary_material_v2
PM5	N/A	Not applicable: APC VCEP PM5 is restricted to residues 1026 and 1028, but p.Ala735Val affects residue 735.	cspec vcep_apc_specifications_supplementary_material_v2
PM6	Not assessed	Not assessed: the single reported occurrence has no documented assumed-de-novo status, parental relationship status, or phenotype-point score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23159591
PP1	Not assessed	Not assessed: no qualifying affected relatives, phenotype points, or segregation meioses are reported for c.2204C>T/p.Ala735Val.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23159591
PP2	Not met	Not met: APC missense variants are not a frequent disease mechanism, and most are benign, likely benign, or VUS under the VCEP description.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: SpliceAI maximum delta 0.00 predicts no significant splice impact, whereas APC missense PP3 requires splicing evidence revealing a possible effect.	cspec vcep_apc_specifications_supplementary_material_v2 spliceai
PP4	N/A	Not applicable: the APC VCEP states PP4 is captured by PS4 and cannot be used independently.	vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: the APC VCEP does not use PP5 without the primary evidence underlying an expert opinion.	vcep_apc_specifications_supplementary_material_v2
BA1	Not met	Not met: non-cancer gnomAD v2.1 exome Popmax FAF is 0.004594%, below the APC VCEP BA1 threshold of at least 0.1%.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS1	Met	Met at Strong: non-cancer gnomAD v2.1 exome Popmax FAF is 0.004594%, exceeding the APC VCEP BS1 threshold of at least 0.001%.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS2	Not met	Not met: non-cancer gnomAD v2.1 exomes report zero homozygotes, and no VCEP-qualified healthy-individual phenotype points are available.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS3	N/A	Not applicable: p.Ala735Val is a missense variant at codon 735, outside the VCEP BS3 protein-assay domain of codons 959-2129.	cspec vcep_apc_specifications_supplementary_material_v2
BS4	Not assessed	Not assessed: no affected member lacking c.2204C>T/p.Ala735Val has a documented APC phenotype-point score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23159591
BP1	Met	Met, supporting: codon 735 is outside the VCEP BP1 exception at codons 1021–1035 for APC missense variants.	cspec vcep_apc_specifications_supplementary_material_v2 PMID:23159591
BP2	Met	Met at Supporting: c.2204C>T was observed once in trans with pathogenic APC p.Arg332Ter (c.994C>T).	cspec PMID:23159591
BP3	N/A	Not applicable: the APC VCEP states BP3 is not used, and c.2204C>T is a missense SNV rather than an in-frame indel.	pvs1_variant_assessment vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: APC BP4 explicitly excludes missense variants, and c.2204C>T produces the missense change p.Ala735Val.	cspec vcep_apc_specifications_supplementary_material_v2
BP5	Not met	Not met: the reported trans variant is pathogenic APC p.Arg332Ter, not a qualifying alternate polyposis-gene variant.	vcep_apc_specifications_supplementary_material_v2 PMID:23159591
BP6	N/A	Not applicable: the APC VCEP does not use BP6 for unsupported expert reports of benignity.	vcep_apc_specifications_supplementary_material_v2
BP7	N/A	Not applicable: BP7 covers only synonymous or intronic variants at or beyond +7/-21, while c.2204C>T is an exonic missense variant.	cspec vcep_apc_specifications_supplementary_material_v2

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