Variant classification summary

NM_000038.6:c.4348C>T

APC · NP_000029.2:p.(Arg1450Ter) · NM_000038.6

GRCh37: chr5:112175639 C>T · GRCh38: chr5:112839942 C>T

Gene: APC Transcript: NM_000038.6

Final call

Likely Pathogenic

PVS1 very strong PS4 supporting

Variant details

Gene

APC

Transcript

NM_000038.6

Protein

NP_000029.2:p.(Arg1450Ter)

gnomAD AF

0.0 (v2.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: the APC VCEP assigns PVS1 very strong to this codon-1450 nonsense variant.

2

Pathogenic evidence: two unrelated FAP probands provide 1.5 phenotype points, meeting the APC VCEP PS4 supporting threshold.

Final determination: APC VCEP Rule20 classifies a variant as Likely Pathogenic when one PVS1 very strong criterion and one qualifying supporting pathogenic criterion are satisfied; here these are PVS1 and PS4.

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	Met	Met, very strong: nonsense codon 1450 lies within the APC VCEP's codon 49–2645 interval assigned full PVS1.	vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 pvs1_variant_assessment cspec PMID:26446593 PMID:21110124
PS1	N/A	Not applicable: the APC VCEP limits PS1 to missense or splice variants, whereas c.4348C>T produces the nonsense change p.Arg1450Ter.	vcep_apc_specifications_supplementary_material_v2 PMID:26446593 PMID:21110124
PS2	Not assessed	Not assessed: two affected probands are reported, but no parental testing or de novo determination is available to assign the VCEP's 1- or 2-point score.	vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:26446593 PMID:21110124
PS3	Not assessed	Not assessed: no exact-variant RNA or qualifying protein assay result is available to meet the APC VCEP PS3 functional-study requirements.	cspec vcep_apc_specifications_supplementary_material_v2
PS4	Met	Met at Supporting: two unrelated FAP probands contribute 1.5 APC phenotype points, matching the VCEP 1–1.5-point Supporting threshold.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:26446593 PMID:21110124
PM1	N/A	Not applicable: the APC VCEP marks PM1 Not Applicable and identifies no approved APC pathogenic missense hotspot or critical-domain route for residue 1450.	vcep_apc_specifications_supplementary_material_v2
PM2	Not assessed	Not assessed: VCEP-required non-cancer gnomAD allele count and frequency are unknown because the query failed.	vcep_apc_specifications_supplementary_material_v2 gnomad_v2
PM3	N/A	Not applicable: the APC VCEP marks PM3 not applicable for familial adenomatous polyposis.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: APC VCEP PM4 is not used, and this variant is nonsense rather than an in-frame or stop-loss change.	vcep_apc_specifications_supplementary_material_v2
PM5	N/A	Not applicable: PM5 is restricted by the APC VCEP to missense variants at positions 1026 or 1028, while this variant is nonsense at Arg1450.	vcep_apc_specifications_supplementary_material_v2
PM6	Not assessed	Not assessed: affected probands are reported, but neither source documents assumed de novo status or the parental information required for the VCEP PM6 score.	vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:26446593 PMID:21110124
PP1	Not assessed	Not assessed: no affected relatives with matching genotypes or segregation data are reported, so the VCEP's minimum 3-meiosis threshold cannot be evaluated.	vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:26446593 PMID:21110124
PP2	N/A	Not applicable: the APC VCEP explicitly marks PP2 Not Applicable, and the case variant is a nonsense rather than missense variant.	vcep_apc_specifications_supplementary_material_v2
PP3	N/A	Not applicable: c.4348C>T is a nonsense variant, while the APC PP3 rule names presumed-missense splicing effects and non-canonical splicing variants.	cspec vcep_apc_specifications_supplementary_material_v2
PP4	N/A	Not applicable: the APC VCEP states PP4 is already captured by PS4 and cannot be used as independent evidence.	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 assessed	Not assessed: the VCEP-required non-cancer gnomAD v2.1 Popmax frequency is unknown because that query failed.	vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS1	Not assessed	Not assessed: the VCEP-required non-cancer gnomAD v2.1 Popmax frequency is unknown, so the 0.001% BS1 threshold cannot be evaluated.	vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS2	Not assessed	Not assessed: VCEP-relevant non-cancer gnomAD homozygote data are unavailable because the query failed.	vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS3	Not assessed	Not assessed: no exact-variant assay demonstrates preserved APC function, comparable beta-catenin activity, or absence of mRNA aberration under the VCEP BS3 requirements.	cspec vcep_apc_specifications_supplementary_material_v2
BS4	Not assessed	Not assessed: no affected noncarrier is documented, so the VCEP's 0.5-point minimum for BS4 Supporting cannot be evaluated.	vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:26446593 PMID:21110124
BP1	N/A	Not applicable: BP1 is a missense criterion, whereas c.4348C>T is a nonsense variant at codon 1450, outside the codon 1021-1035 exception.	vcep_apc_specifications_supplementary_material_v2
BP2	Not assessed	Not assessed: two reports lack documented trans phase, or at least three unknown-phase occurrences with different pathogenic APC variants, required by the VCEP.	cspec vcep_apc_specifications_supplementary_material_v2 PMID:26446593 PMID:21110124
BP3	N/A	Not applicable: APC VCEP BP3 is not used, and the variant is a nonsense substitution rather than an in-frame repeat-region indel.	vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: c.4348C>T is a nonsense variant, whereas APC BP4 addresses synonymous or intronic variants with multiple no-impact splice predictions.	cspec vcep_apc_specifications_supplementary_material_v2
BP5	Not assessed	Not assessed: no alternate pathogenic adenomatous-polyposis gene variant is documented for the required colorectal polyposis phenotype.	vcep_apc_specifications_supplementary_material_v2
BP6	N/A	Not applicable: the APC VCEP does not use BP6 for unsupported benign expert opinions.	vcep_apc_specifications_supplementary_material_v2
BP7	N/A	Not applicable: c.4348C>T is a coding nonsense variant, not the synonymous or intronic variant required by the APC BP7 rule.	cspec vcep_apc_specifications_supplementary_material_v2

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