Variant classification summary

NM_001127511.3:c.3865del

APC · NP_001120983.2:p.(Ile1289Ter) · NM_001127511.3

GRCh37: chr5:112175207 GA>G · GRCh38: chr5:112839510 GA>G

Gene: APC Transcript: NM_001127511.3

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

APC

Transcript

NM_001127511.3

Protein

NP_001120983.2:p.(Ile1289Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127511.3:c.3865del (p.Ile1289Ter) is a frameshift deletion producing a premature termination codon at residue 1289 in the APC gene, where loss of function is the established mechanism for familial adenomatous polyposis (PVS1_VeryStrong). The truncation removes more than half of the protein including all critical C-terminal domains required for beta-catenin regulation and tumor suppression.

2

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the APC VCEP threshold for PM2_Supporting (allele count ≤ 1, AF < 0.001%).

3

Under the InSiGHT APC VCEP v2.1 combination rules (Rule 20), one PVS1_VeryStrong criterion combined with one supporting pathogenic criterion (PM2_Supporting) yields a classification of Likely Pathogenic.

4

OncoKB classifies this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating impact.

Final determination: Rule20 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 v2.1 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	NM_001127511.3:c.3865del is a frameshift deletion resulting in a premature termination codon at p.Ile1289Ter. APC is a gene where loss of function is the established disease mechanism for familial adenomatous polyposis. The truncation at codon 1289 removes more than half of the protein including all critical C-terminal domains (the majority of 20-amino acid beta-catenin binding repeats, all SAMP/axin-binding motifs, the basic domain, and EB1/HDLG binding sites), consistent with complete loss of tumor suppressor function. Per the ClinGen InSiGHT APC VCEP v2.1, null variants in APC where LOF is the known mechanism meet PVS1 at very strong strength.	vcep_apc_specifications_supplementary_material_v2 pvs1_gene_context pvs1_variant_assessment oncokb
PS1	N/A	PS1 applies to missense and splice variants under the APC VCEP. NM_001127511.3:c.3865del is a frameshift/nonsense variant, not a missense or splice variant.
PS2	Not assessed	No de novo observations are documented for NM_001127511.3:c.3865del in the available case materials. De novo scoring per APC VCEP Tables 1 and 2 cannot be performed without proband data.
PS3	Not assessed	No variant-specific functional studies (RNA assays, protein assays) are available for NM_001127511.3:c.3865del. The three publications reviewed discuss APC function at the gene level but do not test or mention this specific variant. Under the APC VCEP, PS3 requires RNA assays showing premature stop or exon skipping, or protein assays within the beta-catenin binding domain — none are available.
PS4	Not assessed	No affected individuals with NM_001127511.3:c.3865del are documented in the available case materials. The variant is absent from ClinVar. Phenotype point scoring per APC VCEP Table 1 cannot be performed without proband data.
PS5	Not met	NM_001127511.3:c.3865del is absent from ClinVar and has not been reported as pathogenic by any reputable source. No independent evaluation of a prior pathogenic assertion is possible.	clinvar
PM1	N/A	The APC VCEP explicitly states PM1 is not applicable. Per the supplementary material: 'Based on our knowledge there are no mutational hotspots in APC and/or functional domains without benign variation suitable for PM1.'	vcep_apc_specifications_supplementary_material_v2
PM2	Met	NM_001127511.3:c.3865del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the APC VCEP PM2_Supporting threshold (allele count ≤ 1 with allele frequency < 0.001%). Under the APC VCEP, PM2 is capped at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	The APC VCEP does not use PM4 due to limited available data. Additionally, NM_001127511.3:c.3865del is a frameshift deletion resulting in a premature stop codon, not an in-frame deletion/insertion, so PM4 would not apply under generic rules either.	vcep_apc_specifications_supplementary_material_v2
PM5	N/A	PM5 under the APC VCEP applies to missense variants at amino acid residues where a different pathogenic missense change has been reported. NM_001127511.3:c.3865del is a frameshift/nonsense variant, not a missense variant. The pm5_candidates analysis confirms variant class is not missense-like.	pm5_candidates
PM6	Not assessed	No assumed de novo observations are documented for NM_001127511.3:c.3865del. De novo scoring per APC VCEP Tables 1 and 2 cannot be performed without proband and parental data.
PP1	Not assessed	No co-segregation data are available for NM_001127511.3:c.3865del. Meiosis counting per APC VCEP rules cannot be performed without family data.
PP2	N/A	The APC VCEP states PP2 is not applicable. Missense variants are not a frequent mechanism of disease in APC; truncating variants are the primary pathogenic mechanism.
PP3	Not met	Under the APC VCEP, PP3 applies only to missense variants (for in silico splicing prediction) or non-canonical splicing variants with multiple deleterious splicing predictions. NM_001127511.3:c.3865del is a frameshift/nonsense variant. SpliceAI predicts no significant splice impact (max delta score 0.02). REVEL and BayesDel are not applicable (not an SNV). PP3 is not met.	spliceai
PP4	N/A	The APC VCEP states PP4 is not applicable. Patient phenotype specificity is already captured by the PS4 specifications.
PP5	N/A	The APC VCEP states PP5 is not applicable, consistent with the ClinGen SVI recommendation (Biesecker et al. 2018).
BA1	Not met	NM_001127511.3:c.3865del is absent from gnomAD. The APC VCEP BA1 threshold is Popmax Filtering AF ≥ 0.1% (0.001), which is not met.	gnomad_v2 gnomad_v4
BS1	Not met	NM_001127511.3:c.3865del is absent from gnomAD. The APC VCEP BS1 threshold is Popmax Filtering AF ≥ 0.001% (0.00001), which is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on healthy adult individuals carrying NM_001127511.3:c.3865del are available. Healthy individual point scoring per APC VCEP rules cannot be performed.
BS3	Not assessed	No variant-specific functional studies demonstrating a benign effect are available for NM_001127511.3:c.3865del. The APC VCEP BS3 rules require RNA assays showing no mRNA aberration or protein assays showing retained function — none are available for this variant.
BS4	Not assessed	No segregation data demonstrating lack of co-segregation are available for NM_001127511.3:c.3865del.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_001127511.3:c.3865del is itself a truncating (frameshift/nonsense) variant. BP1 is not applicable to truncating variants.
BP2	Not assessed	No phase data are available for NM_001127511.3:c.3865del. The APC VCEP BP2 rule requires observation in trans with a (likely) pathogenic APC variant or ≥3 times in unknown phase with different (likely) pathogenic APC variants — neither condition can be evaluated.
BP3	N/A	The APC VCEP states BP3 is not used due to limited available data. BP3 applies to in-frame deletions/insertions in repetitive regions; NM_001127511.3:c.3865del is a frameshift variant.	vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Under the APC VCEP, BP4 is not applicable for missense variants and applies only to synonymous or intronic variants with multiple in silico splicing predictors suggesting no impact. NM_001127511.3:c.3865del is a frameshift/nonsense variant.
BP5	Not assessed	No alternate molecular basis for a colorectal polyposis phenotype has been identified in association with NM_001127511.3:c.3865del. The APC VCEP BP5 rule requires a (likely) pathogenic variant in another adenomatous polyposis gene — no such data are available.
BP6	N/A	The APC VCEP states BP6 is not for use, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splice impact. NM_001127511.3:c.3865del is a frameshift/nonsense variant.

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