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APCc.3865delLikely pathogenic
Print report
Variant interpretation report

APC c.3865del, p.(Ile1289Ter)

NM_001127511.3:c.3865del NP_001120983.2:p.(Ile1289Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About APC

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen APC VCEP v2.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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: matched Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen APC VCEP v2.1, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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%).

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.

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

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion c.3865del creates premature stop at codon 1289 (p.Ile1289Ter)
  • APC is a well-established LOF disease gene for familial adenomatous polyposis
  • Truncation removes all critical C-terminal functional domains (20-aa repeats
  • SAMP motifs
  • basic domain
  • EB1/HDLG binding)
  • OncoKB classifies as Likely Loss-of-function
  • Likely Oncogenic
Still missing
  • Variant is in the last exon (exon 14) of NM_001127511.3
  • potential NMD escape should be noted
  • but the truncated protein would be non-functional regardless due to loss of all critical domains
Sources
vcep_apc_specifications_supplementary_material_v2pvs1_gene_contextpvs1_variant_assessmentoncokb ↗
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 4 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02 (no predicted splicing impact)
  • REVEL and BayesDel not applicable (not an SNV)
Sources
spliceai ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
PS5 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS2 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. Details ▾Hide ▴
Still missing
  • De novo status unknown
  • no proband or parental data available
PS3 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. Details ▾Hide ▴
Evidence considered
  • Three publications reviewed (PMID:11062151
  • PMID:11257105
  • PMID:15561772) provide gene-level functional context but no variant-specific data
Still missing
  • No RNA assay data for this specific variant
  • No protein functional assay data
  • No systematic range characterization spanning codon 1289
PS4 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. Details ▾Hide ▴
Still missing
  • No proband or case-series data available
  • Variant absent from ClinVar
PM6 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. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No co-segregation data are available for NM_001127511.3:c.3865del. Meiosis counting per APC VCEP rules cannot be performed without family data. Details ▾Hide ▴
Still missing
  • No family segregation data available
BS2 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. Details ▾Hide ▴
Still missing
  • No healthy control data available
BS3 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. Details ▾Hide ▴
Still missing
  • No benign functional data available
BS4 No segregation data demonstrating lack of co-segregation are available for NM_001127511.3:c.3865del. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 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. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 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. Details ▾Hide ▴
Still missing
  • No alternate genetic basis data available
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPThe 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.' Details ▾Hide ▴
Sources
vcep_apc_specifications_supplementary_material_v2
PM4 VCEPThe 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. Details ▾Hide ▴
Sources
vcep_apc_specifications_supplementary_material_v2
PM5 N/APM5 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. Details ▾Hide ▴
Sources
pm5_candidates
PP2 VCEPThe 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. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPThe APC VCEP states PP4 is not applicable. Patient phenotype specificity is already captured by the PS4 specifications. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPThe APC VCEP states PP5 is not applicable, consistent with the ClinGen SVI recommendation (Biesecker et al. 2018). Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPThe 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. Details ▾Hide ▴
Sources
vcep_apc_specifications_supplementary_material_v2
BP4 N/AUnder 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. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe APC VCEP states BP6 is not for use, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
APC
Transcript
NM_001127511.3
Coding (HGVS c.)
NM_001127511.3:c.3865del
Protein (HGVS p.)
NP_001120983.2:p.(Ile1289Ter)
GRCh38
chr5:112839510 GA>G
GRCh37
chr5:112175207 GA>G

Gene diagram

Every interpreted variant in APC, mapped onto the exon structure of NM_001127511.3. Select a row to find it on the plot.

APCNM_001127511.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -359 bp
0.000
SpliceAI acceptor gainat +421 bp
0.000
SpliceAI donor lossat -204 bp
0.000
SpliceAI donor gainat +323 bp
0.020
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02 (no predicted splicing impact)
  • REVEL and BayesDel not applicable (not an SNV)
Sources
spliceai ↗
BP4 N/AUnder 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues.
    Immunohistochemical study of APC and beta-catenin expression in normal and neoplastic colonic tissues. Reports that most APC mutations result in truncated protein products and that loss of full-length APC correlates with nuclear beta-catenin accumulation in colorectal cancers. NM_001127511.3:c.3865del was not identified in this paper.
    Does not name this variant
    PMID 11062151 ↗
  • The ABC of APC.
    Comprehensive review of APC gene structure, protein domains, and genotype-phenotype correlations in familial adenomatous polyposis. Documents that >95% of germline APC mutations are nonsense or frameshift resulting in truncated protein, with mutational hotspots at codons 1061 and 1309. NM_001127511.3:c.3865del was not identified in this paper.
    Does not name this variant
    PMID 11257105 ↗
  • Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability.
    Study of dominant effects of truncating APC mutations on proliferation, spindle checkpoint control, survival, and chromosome stability in cell lines. Reports that truncating APC mutations have dominant effects on multiple cellular processes. NM_001127511.3:c.3865del was not identified in the abstract; full text not available for verification.
    Does not name this variant
    PMID 15561772 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.