Variant classification summary

NM_000038.6:c.3927_3931del

APC · NP_000029.2:p.(Glu1309AspfsTer4) · NM_000038.6

GRCh37: chr5:112175211 TAAAAG>T · GRCh38: chr5:112839514 TAAAAG>T

Gene: APC Transcript: NM_000038.6

Final call

VUS

PVS1 very strong PS4 very strong PM6 strong PP5 supporting BS1 strong

Variant details

Gene

APC

Transcript

NM_000038.6

Protein

NP_000029.2:p.(Glu1309AspfsTer4)

gnomAD AF

7.43476919378602e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong applies to the codon-1309 frameshift within the APC VCEP full-PVS1 interval.

2

Pathogenic: PS4 very strong is supported by 29.5 VCEP phenotype points from 59 documented FAP probands.

3

Pathogenic: PM6 strong is supported by two exact-variant parental-origin observations totaling two de novo scores.

4

Supporting: PP5 records the adjudicated expert-panel pathogenic classification but does not determine the combination rule.

5

Likely Benign: BS1 strong is met because the maximum non-cancer gnomAD v2.1 subpopulation frequency exceeds the VCEP threshold.

Final determination: Under the APC VCEP Version 2.1 framework, PVS1 very strong with at least one qualifying strong pathogenic criterion satisfies Rule18 for Pathogenic, BS1 strong satisfies Rule26 for Likely Benign, and the conflict policy converts simultaneous pathogenic and benign rule satisfaction to VUS.

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 at very strong: the frameshift starts at codon 1309, within the APC VCEP's codon 49–2645 interval assigned full PVS1.	cspec pvs1_variant_assessment PMID:14523376
PS1	N/A	Not applicable: the APC VCEP restricts PS1 to missense or splice variants, while this variant is a five-base-pair frameshift.	cspec vcep_apc_specifications_supplementary_material_v2
PS2	Not assessed	Not assessed: two exact-variant de novo entries are reported, but complete case-level maternity, paternity, and phenotype-point documentation is unavailable.	cspec PMID:14523376
PS3	Not assessed	Not assessed: the available record lacks verifiable primary assay results, controls, and a VCEP-defined RNA or protein endpoint for this exact deletion.	vcep_apc_specifications_supplementary_material_v2 PMID:10213492
PS4	Met	Met Very Strong: 59 documented FAP cases provide 29.5 phenotype points, exceeding the VCEP threshold of ≥16; case-control OR was 9,248.98 (95% CI 4,954.19–17,266.93).	cspec vcep_table_1_262 PMID:14523376 gnomad_v4
PM1	N/A	Not applicable: the APC VCEP explicitly marks PM1 Not Applicable, and APC has no domain-table entry in vcep_materials.json.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: non-cancer gnomAD v2.1 reports AF 0.00084558% with allele count 2, above the PM2 threshold of 0.0003%.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
PM3	N/A	Not applicable: the APC VCEP does not use PM3 because familial adenomatous polyposis has autosomal dominant inheritance.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: the APC VCEP explicitly does not use PM4 because of limited available data.	cspec
PM5	N/A	Not applicable: PM5 requires a different missense change at residue 1026 or 1028, whereas this variant is a frameshift at residue 1309.	cspec vcep_apc_specifications_supplementary_material_v2
PM6	Met	Met, provisionally Strong: two exact-variant parental-origin entries support 2 de novo scores, matching the VCEP's 2-3.5 Strong range.	cspec PMID:14523376
PP1	Not assessed	Not assessed: no affected relatives with the variant or count of segregating meioses is reported for c.3927_3931del.	cspec
PP2	N/A	Not applicable: the APC VCEP marks PP2 Not Applicable, and this variant is a frameshift rather than a missense variant.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	N/A	Not applicable: c.3927_3931del is a coding frameshift, whereas APC PP3 covers presumed missense or non-canonical splicing variants.	cspec vcep_apc_specifications_supplementary_material_v2
PP4	N/A	Not applicable: the APC VCEP states that PP4 is captured by PS4 and cannot be used independently.	cspec
PP5	Met	Not applicable: the APC VCEP states that PP5 is not used for this VCEP.	cspec clinvar
BA1	Not met	Not met: the highest non-cancer gnomAD v2.1 subpopulation AF is 0.017857%, below the APC VCEP BA1 threshold of 0.1%.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS1	Met	Met, Strong: non-cancer gnomAD v2.1 subpopulation AF is 0.017857%, exceeding the APC VCEP BS1 threshold of 0.001%.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes, but healthy-individual points cannot be determined without clinical phenotype data.	cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
BS3	Not assessed	Not assessed: no qualifying benign RNA or protein assay demonstrates normal APC function or splicing for this codon-1309 frameshift.	vcep_apc_specifications_supplementary_material_v2
BS4	Not assessed	Not assessed: no affected noncarrier with a qualifying APC phenotype point is reported for c.3927_3931del.	cspec
BP1	N/A	Not applicable: BP1 is restricted to missense variants, while c.3927_3931del is a five-base-pair frameshift producing p.(Glu1309AspfsTer4).	cspec vcep_apc_specifications_supplementary_material_v2
BP2	Not assessed	Not assessed: no documented in-trans or qualifying unknown-phase co-occurrence with a different (Likely) Pathogenic APC variant is available.	cspec vcep_apc_specifications_supplementary_material_v2
BP3	N/A	Not applicable: the APC VCEP explicitly does not use BP3 because of limited available data.	cspec
BP4	N/A	Not applicable: c.3927_3931del is a coding frameshift, while APC BP4 covers synonymous or intronic variants with no predicted splice impact.	cspec vcep_apc_specifications_supplementary_material_v2
BP5	Not assessed	Not assessed: testing or results for the VCEP-required alternate pathogenic polyposis-gene basis are unavailable.	cspec
BP6	N/A	Not applicable: the APC VCEP states that BP6 is not for use in this VCEP.	cspec
BP7	N/A	Not applicable: c.3927_3931del is a coding frameshift, not the synonymous or intronic variant required by APC BP7.	cspec vcep_apc_specifications_supplementary_material_v2

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