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APCc.3920T>ABenign
Print report
Variant interpretation report

APC c.3920T>A, p.Ile1307Lys

NM_000038.6:c.3920T>A NP_000029.2:p.(Ile1307Lys) Missense · exon 16 View identifiers
Classification
Benign

Variant description:

The APC NM_000038.6:c.3920T>A (NP_000029.2:p.(Ile1307Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV57326270, n = 23 times). Experimental evidence: I1307K showed compromised beta-catenin-regulated transcription in at least 10 independent luciferase experiments, satisfying the VCEP protein-assay PS3 rule. Based on available guidelines, this variant is considered to be Benign.

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

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About APC

APC is a tumor suppressor gene whose protein acts as a key brake on the Wnt signaling pathway by helping mark the growth-promoting protein beta-catenin for destruction; it also participates in cell migration, adhesion, and apoptosis. Inherited mutations in APC cause familial adenomatous polyposis (FAP), an autosomal dominant condition characterized by numerous colorectal polyps and a very high risk of colorectal cancer, with related forms including attenuated FAP and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Somatic APC mutations are found in roughly 50-80% of sporadic colorectal cancers, where they act as early tumor-initiating events, and are also observed in some breast, stomach, and prostate cancers. Loss of APC function leaves Wnt signaling abnormally active, driving uncontrolled cell growth, which makes APC a central tumor suppressor in colorectal cancer.

NCBI Gene ↗ OncoKB ↗
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: 1 Benign evidence criteria: 3
Pathogenic criteria applied · 1
PS3Supporting
PS3 · supporting

Met, Supporting: I1307K showed compromised beta-catenin-regulated transcription in at least 10 independent luciferase experiments, satisfying the VCEP protein-assay PS3 rule.

Benign criteria applied · 3
BS1Strong
BS1 · strong

Met, Strong: non-cancer gnomAD v2.1.1 Popmax FAF is 0.054599%, exceeding the APC VCEP BS1 threshold of 0.001%.

BS2Strong
BS2 · strong

Met, Strong: the non-cancer gnomAD v2.1.1 dataset reports 7 homozygotes, exceeding the APC VCEP requirement of at least 2.

BP1Supporting
BP1 · supporting

Met, Supporting: p.Ile1307Lys is a missense variant at codon 1307, outside the APC VCEP BP1 exception spanning codons 1021–1035.

Recorded classification: Benign

Benign: BS1 (strong) and BS2 (strong) satisfy the APC VCEP's Rule26; PS3 and BP1 do not satisfy a pathogenic rule.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
2,000 / 1,614,038 alleles

gnomAD v4.1: 2,000 / 1,614,038 alleles. Recorded AF 0.00123913. Recorded homozygote count 29.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00185541; MAF= 0.18554%, 524/282418 alleles, homozygotes = 7) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0362039; MAF= 3.62039%, 375/10358 alleles, homozygotes = 7); grpmax FAF= 0.00056452.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.002985884907709012, 55/18420 alleles, homozygotes = 1).

Applied · BS1, BS2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.233 recorded score

Recorded REVEL score: 0.233. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
47 reported laboratory submissions

20 Uncertain significance · 8 Likely pathogenic · 7 risk factor · 5 Established risk allele · 4 Pathogenic · 1 association · 1 pathogenic · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.

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.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
23 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57326270, n = 23 times).

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: 4 met · 7 not met · 6 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

Population criteria: BS1 Strong and BS2 Strong are met; BA1 and PM2 are not met under the APC VCEP v2.1 population rules.

Met · 4

PS3 SupportingVCEPMet, Supporting: I1307K showed compromised beta-catenin-regulated transcription in at least 10 independent luciferase experiments, satisfying the VCEP protein-assay PS3 rule. Details ▾Hide ▴
Reasoning

PS3_Supporting is met. The APC VCEP permits Supporting PS3 when protein assays show increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding by surface plasmon resonance for variants within the beta-catenin binding domain, codons 959-2129. NM_000038.6:c.3920T>A (p.Ile1307Lys, p.I1307K) changes codon 1307 and therefore lies within that domain. PMID:18199528 directly studied I1307K using beta-catenin-regulated transcription luciferase assays in SW480 APC-deficient cells, averaged over at least 10 independent experiments, and reported that I1307K was functionally compromised with reduced ability to suppress transcription. This is validated variant-specific protein-function evidence supporting a damaging effect and meets the VCEP Supporting branch; it does not meet the RNA-based stronger branches.

VCEP rule
**Protein assays** show Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_) [Reference 2].
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PS3 Supporting row: protein assays showing increased beta-catenin-regulated transcription activity and/or decreased binding to beta-catenin by surface plasmon resonance support PS3 for variants in the APC beta-catenin binding domain, codons 959-2129.
  • Variant normalization: NM_000038.6:c.3920T>A produces NP_000029.2:p.(Ile1307Lys) / p.(I1307K), placing the altered codon 1307 within the VCEP-defined beta-catenin binding domain.
  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predict a colorectal cancer risk, PMID:18199528, Results section 'Functional analyses of nonsynonymous variants in the beta-catenin down-regulating domain': I1307K was tested in beta-catenin-regulated transcription luciferase assays in SW480 APC-deficient cells, averaged over at least 10 independent experiments, and showed compromised function with reduced ability to suppress transcription.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗PMID:18199528 ↗
BS1 StrongVCEPMet, Strong: non-cancer gnomAD v2.1.1 Popmax FAF is 0.054599%, exceeding the APC VCEP BS1 threshold of 0.001%. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS1 Strong at a gnomAD Popmax Filtering Allele Frequency of at least 0.001% (0.00001), preferably using the gnomAD v2.1.1 non-cancer dataset. The variant's non-cancer Popmax Filtering Allele Frequency is 0.00054599 (0.054599%), exceeding 0.00001; therefore BS1 Strong is met. The APC supplementary specification was searched for c.3920T>A, p.Ile1307Lys, and p.I1307K, with no variant-specific entry found.

VCEP rule
GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.001%** (0.00001).
Evidence considered
  • APC VCEP CSPEC BS1 Strong rule: GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.001% (0.00001).
  • APC_specifications_supplementary-material_V2.pdf, BS1 row: allele frequency ≥ 0.001%, preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD v2.1.1.
  • GNOMAD_V2_1_NON_CANCER, variant 5-112175211-T-A: non-cancer exomes AF 0.0020124807630515296; Popmax Filtering Allele Frequency 0.00054599 (0.054599%); 476/236524 alleles; 7 homozygotes.
Still missing
  • No variant-specific entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.txt; the generic VCEP BS1 rule was applied.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS2 StrongVCEPMet, Strong: the non-cancer gnomAD v2.1.1 dataset reports 7 homozygotes, exceeding the APC VCEP requirement of at least 2. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS2 Strong when there are at least 10 healthy-individual points or at least 2 observations in the homozygous state, and permits the gnomAD v2.1.1 non-cancer dataset to search for homozygous individuals. This variant is observed in 7 homozygotes in that dataset, satisfying the homozygous-state path; therefore BS2 Strong is met. The APC supplementary specification was searched for c.3920T>A, p.Ile1307Lys, and p.I1307K, with no variant-specific entry found.

VCEP rule
≥ 10 points for healthy individuals **OR** ≥ 2 times in homozygous state.
Evidence considered
  • APC VCEP CSPEC BS2 Strong rule: ≥ 10 points for healthy individuals OR ≥ 2 times in homozygous state.
  • APC_specifications_supplementary-material_V2.pdf, BS2 row: the non-cancer gnomAD v2.1.1 dataset cannot be used for heterozygous healthy individuals but can be used to search for homozygous individuals.
  • GNOMAD_V2_1_NON_CANCER, variant 5-112175211-T-A: 7 homozygotes in non-cancer exomes (476/236524 alleles; AF 0.0020124807630515296).
Still missing
  • No variant-specific entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.txt; the generic VCEP BS2 rule was applied.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BP1 SupportingVCEPMet, Supporting: p.Ile1307Lys is a missense variant at codon 1307, outside the APC VCEP BP1 exception spanning codons 1021–1035. Details ▾Hide ▴
Reasoning

BP1 is met at Supporting strength. The variant is a missense SNV at residue 1307, and the APC VCEP states that BP1 is applicable except for missense variants in codons 1021-1035, the first 15-amino-acid repeat of the β-catenin binding domain. Residue 1307 lies outside that exception, so the VCEP BP1 rule applies.

VCEP rule
BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035).
Evidence considered
  • Variant normalization: NM_000038.6:c.3920T>A; NP_000029.2:p.(Ile1307Lys) / p.(I1307K); missense SNV at codon 1307.
  • CSPEC BP1 rule: BP1 is applicable to APC except for missense variants in codons 1021-1035.
  • APC_specifications_supplementary-material_V2.pdf, BP1 row: APC is primarily affected by truncating disease-causing variants and BP1 is prohibited only within codons 1021-1035; codon 1307 is outside that interval.
  • No exact variant row was found when searching c.3920T>A, p.Ile1307Lys, and p.I1307K in the governing APC supplementary file.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Not met · 7 · evaluated, threshold not reached

PS1 VCEPNot met: p.Ile1307Lys is at residue 1307, whereas the APC VCEP limits missense PS1 use to established changes at residues 1026 or 1028. Details ▾Hide ▴
Reasoning

PS1 is not met. NM_000038.6:c.3920T>A produces p.Ile1307Lys (p.I1307K), but the APC VCEP identifies only p.Asn1026Ser and p.Ser1028Arg as currently established Likely Pathogenic missense changes eligible for the PS1_Moderate route; residue 1307 is neither position and no previously established pathogenic variant with the same amino-acid change was identified. The exact notations c.3920T>A, p.Ile1307Lys, and p.I1307K were searched in APC_specifications_supplementary-material_V2.pdf.txt and no exact variant entry was found.

VCEP rule
Based on the current knowledge there are only two amino acid positions (1026 and 1028), where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) , located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). Thus, PS1_Moderate can currently only be used for missense variants at these two amino acid positions.
Evidence considered
  • Variant normalization: NM_000038.6:c.3920T>A; NP_000029.2:p.(Ile1307Lys) / p.(I1307K); missense SNV at residue 1307.
  • APC_specifications_supplementary-material_V2.pdf, PS1 row: the only currently recognized Likely Pathogenic APC missense positions are 1026 and 1028, and PS1_Moderate can currently only be used at those two positions.
  • No exact variant row was found when searching c.3920T>A, p.Ile1307Lys, and p.I1307K in the governing APC supplementary file.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PS4 VCEPNot met: verified studies showed OR 1.35 (95% CI 0.48-3.82), OR 0.21 (0.05-0.81), and OR 3.01 (0.38-23.61), without consistent significant enrichment. Details ▾Hide ▴
Reasoning

The APC VCEP defines PS4 as increased prevalence in affected individuals versus controls and assigns strength from phenotype points. No variant-specific pre-assigned PS4 code was found in APC_specifications_supplementary-material_V2.pdf or Table-1%262.pdf. Verified exact-variant publications do not establish the required significant enrichment: PMID:18199528 reported 6/480 cases versus 9/969 controls (OR 1.35, 95% CI 0.48-3.82), PMID:9724771 reported 3/164 patients versus 8/98 controls (OR 0.21, 95% CI 0.05-0.81, favoring controls), and PMID:10938175 reported 22/161 adenoma patients versus 1/20 hyperplastic-polyp patients (OR 3.01, 95% CI 0.38-23.61). PMID:18343606 reported 1/48 CRC cases versus 0/63 controls, for which the uncorrected OR is undefined; this isolated result does not establish significant enrichment. The verified evidence therefore does not meet the VCEP PS4 requirement.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls ... 4-15.5 phenotype points. For phenotype points curation see **Table 1**.
Evidence considered
  • APC VCEP supplementary specification: PS4 is defined as prevalence in affected individuals being significantly increased compared with controls; the source states that its modifications are based on Fortuno et al. 2020 (PMID:33300245).
  • APC VCEP Table 1, phenotype-point row system and Table 2, point-to-strength system; no row for c.3920T>A, p.Ile1307Lys, or p.I1307K was present in the searched full text.
  • PMID:18199528, Table 1 and Results: 6 of 480 non-FAP/non-MAP colorectal-adenoma patients versus 9 of 969 healthy controls carried I1307K; computed OR=1.35, 95% CI=0.48-3.82.
  • PMID:9724771, Results: 3 I1307K carriers among 164 patients with multiple colorectal adenomas and/or colorectal cancer versus 8 among 98 unselected Ashkenazi controls; computed OR=0.21, 95% CI=0.05-0.81.
  • PMID:10938175, Results/Tables 2-3: 22 of 161 Ashkenazi Jewish adenomatous-polyp patients versus 1 of 20 hyperplastic-polyp patients carried I1307K; computed OR=3.01, 95% CI=0.38-23.61.
  • PMID:18343606, Results: 1 of 48 Tunisian CRC cases versus 0 of 63 healthy controls carried I1307K; the uncorrected OR is undefined because the control-variant cell is zero.
Still missing
  • No exact-variant pre-assigned PS4 code was found in APC_specifications_supplementary-material_V2.pdf.
  • No exact-variant pre-assigned PS4 code was found in Table-1%262.pdf.
  • literature_pass.json packet.ai_classified_papers also listed PMID:26421687 (reported adjusted OR 2.53) and PMID:9288102 (reported approximately 28% versus 6%), but neither PMID had a paper_extracts.json entry, source_registry key, abstract, or fetched full text available for independent verification; these leads were not used as evidence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:10938175 ↗PMID:9724771 ↗PMID:18199528 ↗PMID:18343606 ↗
PM2 VCEPNot met: non-cancer gnomAD v2.1.1 AF is 0.201248% with 476 alleles, exceeding the APC VCEP PM2 threshold of 0.0003%. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PM2 Supporting using the total population from the gnomAD v2.1.1 non-cancer dataset: allele frequency ≤ 0.0003% (0.000003) when allele count is greater than 1, or below 0.001% (0.00001) when allele count is at most 1. The variant has 476 alternate alleles and AF 0.0020124807630515296 (0.201248%), which exceeds the applicable 0.0003% threshold; therefore PM2 is not met. The APC supplementary specification was searched for c.3920T>A, p.Ile1307Lys, and p.I1307K, with no variant-specific entry found.

VCEP rule
Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1.
Evidence considered
  • APC VCEP CSPEC PM2 Supporting rule: Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1.
  • APC_specifications_supplementary-material_V2.pdf, PM2 row: total population from the non-cancer dataset from gnomAD v2.1.1 is recommended; the specification sets ≤ 0.0003% for allele count > 1 and < 0.001% for allele count ≤ 1.
  • GNOMAD_V2_1_NON_CANCER, variant 5-112175211-T-A: total non-cancer exomes AF 0.0020124807630515296 (0.201248%), 476/236524 alleles, 7 homozygotes.
Still missing
  • No variant-specific entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.txt; the generic VCEP PM2 rule was applied.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
PM5 VCEPNot met: PM5 is limited to APC residues 1026 and 1028, while p.Ile1307Lys affects residue 1307 and has no VCEP-qualified same-residue comparator. Details ▾Hide ▴
Reasoning

PM5 is not met. The APC VCEP restricts this criterion to missense variants at residues 1026 and 1028, where the specified Likely Pathogenic variants p.Asn1026Ser and p.Ser1028Arg provide the comparator framework; p.Ile1307Lys is at residue 1307 and no qualifying same-residue pathogenic comparator is established by the VCEP. The exact notations c.3920T>A, p.Ile1307Lys, and p.I1307K were searched in APC_specifications_supplementary-material_V2.pdf.txt and no exact variant entry was found.

VCEP rule
Based on the current knowledge this criterion can only be used for missense variants at the two amino acid positions 1026 and 1028, where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) (for details see PS1).
Evidence considered
  • Variant normalization: NM_000038.6:c.3920T>A; NP_000029.2:p.(Ile1307Lys) / p.(I1307K); residue 1307.
  • APC_specifications_supplementary-material_V2.pdf, PM5 row: PM5 can only be used for missense variants at residues 1026 and 1028, represented by c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg).
  • No exact variant row was found when searching c.3920T>A, p.Ile1307Lys, and p.I1307K in the governing APC supplementary file.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PP3 VCEPNot met: SpliceAI maximum delta score is 0.00, indicating no significant splice impact for this missense variant under the APC VCEP PP3 path. Details ▾Hide ▴
Reasoning

The APC VCEP PP3 rule excludes conservation and evolutionary models for missense variants and directs use of in silico splicing predictors to reveal possible splicing effects. This variant is a missense change, and the governing evidence reports SpliceAI DS_AG, DS_AL, DS_DG, and DS_DL values of 0.00, with a maximum delta score of 0.00 and no significant splice impact. Therefore, the named computational path does not support a deleterious splicing effect and PP3 is not met. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects.
Evidence considered
  • ClinGen APC CSPEC PP3 missense rule: do not use conservation or evolutionary computational models; use in silico splicing predictors for presumed missense variants to reveal possible splicing effects.
  • APC_specifications_supplementary-material_V2.pdf, PP3 row: the APC VCEP excludes computational prediction models for conservation/evolution in missense variants and lists SpliceAI among recommended splice prediction programs.
  • SpliceAI result for NM_000038.6:c.3920T>A / NP_000029.2:p.(Ile1307Lys): DS_AG=0.00, DS_AL=0.00, DS_DG=0.00, DS_DL=0.00; maximum delta score=0.00; reported as no significant splice impact.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗spliceai ↗
BA1 VCEPNot met: non-cancer gnomAD v2.1.1 Popmax FAF is 0.054599%, below the APC VCEP BA1 threshold of 0.1%. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BA1 at a gnomAD Popmax Filtering Allele Frequency of at least 0.1% (0.001), preferably using the gnomAD v2.1.1 non-cancer dataset. In that governing population source, the variant has a Popmax Filtering Allele Frequency of 0.00054599 (0.054599%), below 0.001%; therefore BA1 is not met. The APC supplementary specification was searched for c.3920T>A, p.Ile1307Lys, and p.I1307K, with no variant-specific entry found.

VCEP rule
GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.1%** (0.001).
Evidence considered
  • APC VCEP CSPEC BA1 rule: GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.1% (0.001).
  • APC_specifications_supplementary-material_V2.pdf, BA1 row: allele frequency ≥ 0.1%, preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD v2.1.1.
  • GNOMAD_V2_1_NON_CANCER, variant 5-112175211-T-A: non-cancer exomes AF 0.0020124807630515296; Popmax Filtering Allele Frequency 0.00054599 (0.054599%); 476/236524 alleles; 7 homozygotes.
Still missing
  • No variant-specific entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.txt; the generic VCEP BA1 rule was applied.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS3 VCEPNot met: I1307K showed compromised rather than wild-type-comparable beta-catenin transcriptional function in the reported protein assay. Details ▾Hide ▴
Reasoning

BS3 is not met. The APC VCEP Supporting BS3 branch requires a protein assay showing retention of beta-catenin-regulated transcription activity comparable to wild-type for a variant within codons 959-2129. Although I1307K lies within that domain, PMID:18199528 reports the opposite result: the beta-catenin-regulated transcription assay found I1307K functionally compromised, with reduced ability to suppress transcription. Therefore the available variant-specific assay does not show retained wild-type function and cannot support BS3. The Strong RNA branch is also not applicable because this is a missense variant and no qualifying RNA assay is reported.

VCEP rule
**Protein assay** show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_, see PMID: 33348689)
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, BS3 Supporting row: a protein assay must show retention of beta-catenin-regulated transcription activity comparable to wild-type for variants in APC codons 959-2129; the BS3 Strong row is restricted to qualifying RNA assays of synonymous or intronic variants.
  • Variant normalization: NM_000038.6:c.3920T>A produces p.(Ile1307Lys) / p.(I1307K), within codons 959-2129 but not a synonymous or intronic variant.
  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predict a colorectal cancer risk, PMID:18199528, functional-analysis result: 'Both I1307K and E1317Q were found to be functionally compromised.' The reported assay context was beta-catenin-regulated transcription luciferase testing in SW480 APC-deficient cells, averaged over at least 10 independent experiments.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗PMID:18199528 ↗

Not assessed · 6 · no assessment recorded

PS2 VCEPNot assessed: no confirmed parental relationships, phenotype-point assignment, or VCEP de novo score is available for this variant. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PS2 from de novo scores curated using Tables 1 and 2. Available I1307K reports provide cohort carrier observations but no case-level confirmation of maternity and paternity, parental testing, phenotype-point assignment, or de novo score. The variant was not found under c.3920T>A, p.Ile1307Lys, or p.I1307K in APC_specifications_supplementary-material_V2.pdf or Table-1%262.pdf.

VCEP rule
PS2 de novo scoring under the APC VCEP, with score curation in Tables 1 and 2
Evidence considered
  • The VCEP CSPEC entry assigns PS2 as Very Strong at ≥4, Strong at 2–3.5, and Moderate at 1–1.5 de novo scores, with curation delegated to Tables 1 and 2.
  • PMID:9724771 reports three heterozygous I1307K carriers among patients with multiple colorectal adenomas but no parental testing or segregation evidence.
  • PMID:10938175 reports I1307K in 22 of 161 Ashkenazi Jewish patients with adenomatous polyps but no confirmed de novo observation or parental testing.
  • PMID:18343606 reports one I1307K carrier among 48 unrelated colorectal-cancer patients and no segregation analysis.
Still missing
  • No case-level parental testing or confirmed maternity and paternity was available.
  • No VCEP phenotype-point or de novo-score assignment was available.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in Table-1%262.pdf.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:9724771 ↗PMID:10938175 ↗PMID:18343606 ↗
PM6 VCEPNot assessed: no assumed-de-novo proband record, parental-relationship information, phenotype points, or VCEP de novo score is available. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PM6 from de novo scores curated using Tables 1 and 2, with parental-relationship status affecting the score. Available I1307K reports provide cohort carrier observations but no proband-level assumed-de-novo record, parental-relationship information, phenotype-point assignment, or de novo score. The variant was not found under c.3920T>A, p.Ile1307Lys, or p.I1307K in APC_specifications_supplementary-material_V2.pdf or Table-1%262.pdf.

VCEP rule
PM6 de novo scoring under the APC VCEP, with score curation in Tables 1 and 2
Evidence considered
  • The VCEP CSPEC entry assigns PM6 as Strong at 2–3.5, Moderate at 1–1.5, and Supporting at 0.5 de novo scores, with curation delegated to Tables 1 and 2.
  • The reviewed I1307K reports describe affected or population cohorts rather than a proband-level assumed-de-novo finding with parental-relationship information.
  • PMID:18343606 explicitly reports no segregation analysis for the I1307K carrier.
Still missing
  • No proband-level assumed-de-novo observation with parental-relationship status was available.
  • No VCEP phenotype-point or de novo-score assignment was available.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in Table-1%262.pdf.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:9724771 ↗PMID:10938175 ↗PMID:18343606 ↗
PP1 VCEPNot assessed: no family pedigree or informative meiosis count demonstrates cosegregation of c.3920T>A with the APC phenotype. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PP1 from documented cosegregation measured in meioses: Supporting for 3–4, Moderate for 5–6, and Strong for at least 7 meioses in at least 2 families. Available I1307K reports provide cohort carrier observations but no family pedigree, affected relatives, informative meioses, or segregation result. The variant was not found under c.3920T>A, p.Ile1307Lys, or p.I1307K in APC_specifications_supplementary-material_V2.pdf or Table-1%262.pdf.

VCEP rule
PP1 cosegregation under the APC VCEP, scored by informative meioses and number of families
Evidence considered
  • The APC VCEP PP1 thresholds are 3–4 segregating meioses for Supporting, 5–6 for Moderate, and ≥7 meioses in ≥2 families for Strong.
  • PMID:9724771 reports three heterozygous I1307K carriers but no family segregation analysis.
  • PMID:10938175 reports cohort carrier rates but no informative meioses or cosegregation results.
  • PMID:18343606 explicitly reports no segregation analysis.
Still missing
  • No family-level segregation data or informative meiosis count was available.
  • No affected-relative genotypes and phenotypes were available to establish cosegregation.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in Table-1%262.pdf.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:9724771 ↗PMID:10938175 ↗PMID:18343606 ↗
BS4 VCEPNot assessed: no affected noncarrier with VCEP-assigned phenotype points demonstrates non-segregation of the APC variant. Details ▾Hide ▴
Reasoning

The APC VCEP requires BS4 evidence from an affected member without the variant who meets the specified phenotype-point threshold, or from at least two such affected members meeting the lower threshold. No family-level non-segregation observation, affected noncarrier genotype, or VCEP phenotype-point assignment is available. The variant was not found under c.3920T>A, p.Ile1307Lys, or p.I1307K in APC_specifications_supplementary-material_V2.pdf or Table-1%262.pdf.

VCEP rule
BS4 non-segregation under the APC VCEP, using affected noncarrier phenotype points from Table 1
Evidence considered
  • The APC VCEP BS4 rule requires one affected member without the variant scoring at least 1 phenotype point, or at least two affected noncarriers each scoring at least 0.5 phenotype points; Supporting requires one affected noncarrier scoring at least 0.5.
  • The reviewed I1307K publications report cohort carrier observations but no affected family members lacking the variant with the required phenotype-point assessment.
  • PMID:18343606 reports unrelated cases and controls and no segregation analysis.
Still missing
  • No affected family member without the variant was documented.
  • No phenotype-point assessment was available for any affected noncarrier.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in APC_specifications_supplementary-material_V2.pdf.
  • No entry for c.3920T>A, p.Ile1307Lys, or p.I1307K was found in Table-1%262.pdf.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:9724771 ↗PMID:10938175 ↗PMID:18343606 ↗
BP2 VCEPNot assessed: Table 1 reports I1307K in 2 FAP patients, but establishes neither an in-trans pathogenic APC partner nor ≥3 qualifying unknown-phase observations. Details ▾Hide ▴
Reasoning

The APC VCEP permits BP2 only when the variant is observed in trans with a (Likely) Pathogenic APC variant, or when observed at least 3 times in an unknown phase with different (Likely) Pathogenic APC variants. PMID:18199528 reports I1307K in 2 FAP patients in Table 1, but does not identify a qualifying pathogenic APC partner, establish phase, or provide at least 3 qualifying unknown-phase observations. Therefore BP2 cannot be evaluated from the available evidence.

VCEP rule
Observed _in trans_ with a (Likely) Pathogenic _APC_ variant **OR** ≥ 3 times in an unknown phase with different (Likely) Pathogenic _APC_ variants.
Evidence considered
  • ClinGen InSiGHT APC VCEP CSPEC entry for BP2: Supporting requires observation in trans with a (Likely) Pathogenic APC variant or at least 3 observations in unknown phase with different (Likely) Pathogenic APC variants.
  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas, PMID:18199528, Table 1, FAP patients row: I1307K (2); the table does not specify a pathogenic APC partner or phase for those observations.
Still missing
  • No documented in-trans phase with a (Likely) Pathogenic APC variant.
  • No documented set of at least 3 observations with different (Likely) Pathogenic APC variants in unknown phase.
Sources
cspec ↗PMID:18199528 ↗
BP5 VCEPNot assessed: the VCEP requires a qualifying alternate polyposis-gene basis, but no such second genetic diagnosis is documented. Details ▾Hide ▴
Reasoning

The APC VCEP limits BP5 to an alternate genetic basis of the colorectal polyposis phenotype. The available evidence bundle and reviewed exact-variant papers do not document a qualifying pathogenic or likely pathogenic variant in another adenomatous-polyposis gene in this case, so BP5 cannot be evaluated.

VCEP rule
(Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous variants in _POLD1_ or _POLE_; biallelic variants in _MUTYH, NTHL1_ or _MSH3_; in patients with onset in childhood / adolescence: biallelic variants in _MLH1, MSH2, MSH6_ or _PMS2_). This rule is only applicable when a colorectal polyposis phenotype is present.
Evidence considered
  • APC VCEP CSPEC BP5 instruction: the rule is for a pathogenic or likely pathogenic variant in another adenomatous polyposis gene and applies only when a colorectal polyposis phenotype is present.
  • APC_specifications_supplementary-material_V2.pdf, BP5 row: only applicable for an alternate molecular basis of the colorectal polyposis phenotype.
Still missing
  • No qualifying alternate pathogenic or likely pathogenic variant in another adenomatous-polyposis gene was documented in the available case evidence.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.3920T>A is a missense SNV, whereas the APC VCEP PVS1 rule applies to null variants such as nonsense, frameshift, splice, or deletion variants. Details ▾Hide ▴
Reasoning

PVS1 is not applicable because NM_000038.6:c.3920T>A (p.Ile1307Lys, p.I1307K) is a missense SNV in exon 16, not a null variant. The APC VCEP PVS1 specification is restricted to null variants, and its Figure 1 paths cover nonsense/frameshift, splice, deletion, duplication, and initiation-codon variants; this missense variant is outside those paths. The exact notations c.3920T>A, p.Ile1307Lys, and p.I1307K were searched and were not found in APC_specifications_supplementary-material_V2.pdf.txt or Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf.txt.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... APC is a gene where LOF is the predominant mechanism of disease.
Evidence considered
  • Variant-level assessment: NM_000038.6:c.3920T>A; NP_000029.2:p.(Ile1307Lys) / p.(I1307K); exon 16; missense; canonical splice consensus false.
  • APC_specifications_supplementary-material_V2.pdf, PVS1 row: the original criterion is a null variant, and the APC VCEP states that APC is a gene where LOF is the predominant mechanism of disease.
  • Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf, Figure 1(A): the listed PVS1 paths are nonsense/frameshift, splice, deletion, duplication, and initiation-codon variants; a missense SNV is not one of the listed variant classes.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf.txt.
Sources
pvs1_variant_assessmentvcep_apc_specifications_supplementary_material_v2 ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 ↗
PM1 VCEPNot applicable: the APC VCEP marks PM1 not applicable and identifies no approved APC missense hotspot or critical-domain route covering residue 1307. Details ▾Hide ▴
Reasoning

PM1 is not applicable under the APC VCEP. Its CSPEC entry explicitly marks PM1 not applicable, the authoritative vcep_materials.json domain_tables object has no APC domain-table entry, and the governing supplementary specification states that residues 1026 and 1028 are not enough to define a mutational hotspot, with no other known pathogenic missense germline hotspots and somatic data excluded for APC. Residue 1307 therefore cannot qualify through a VCEP-approved hotspot or critical-domain route.

VCEP rule
Based on our knowledge there are only two amino acid positions (1026 and 1028), where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) (for details see PS1). However, until now there is not enough evidence to define this as a mutational hotspot. There are no other known mutational hotspots for pathogenic missense germline variants in APC.
Evidence considered
  • CSPEC PM1 entry: applicability is Not applicable.
  • vcep_materials.json domain_tables: no APC entry is present.
  • APC_specifications_supplementary-material_V2.pdf, PM1 row: positions 1026 and 1028 are not enough to define a mutational hotspot; there are no other known mutational hotspots for pathogenic missense germline variants in APC, and somatic variant data could not be used for APC.
  • No exact variant row was found when searching c.3920T>A, p.Ile1307Lys, and p.I1307K in the governing APC supplementary file.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM3 VCEPNot applicable: the APC VCEP explicitly marks PM3 as not applicable for this autosomal-dominant condition. Details ▾Hide ▴
Reasoning

The APC VCEP marks PM3 as not applicable. APC-associated polyposis is governed as an autosomal dominant condition in the case framework, so recessive-disorder evidence from affected individuals carrying variants in trans is not used.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT APC VCEP CSPEC entry for PM3: applicability is explicitly listed as Not Applicable.
  • The case framework identifies the preferred mode of inheritance as autosomal dominant inheritance for familial adenomatous polyposis 1.
Sources
cspec ↗final_classification_framework
PM4 VCEPNot applicable: the APC VCEP explicitly does not use PM4 due to limited available data, and this missense SNV causes no protein-length change. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the APC VCEP specification because the VCEP explicitly states that PM4 is not used due to limited available data. Independently, the variant is a missense SNV with no protein-length change: p.Ile1307Lys changes one amino acid without an in-frame insertion, deletion, or stop-loss event.

VCEP rule
Not used due to limited available data.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PM4 row: 'Not used due to limited available data.'
  • Variant-level assessment: the consequence is missense and the protein change is p.Ile1307Lys, not an in-frame insertion/deletion or stop-loss protein-length change.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗pvs1_variant_assessment
PP2 VCEPNot applicable: the APC VCEP marks PP2 not applicable because missense variants are not a frequent APC mutation type and most are benign, likely benign, or VUS. Details ▾Hide ▴
Reasoning

PP2 is not applicable under the APC VCEP. The CSPEC entry explicitly marks PP2 not applicable, and the supplementary specification explains that missense variants are not a frequent mutation type in APC, while most are benign, likely benign, or VUS and only two positions have reported Likely Pathogenic missense variants.

VCEP rule
Missense variants are not a frequent mutation type in APC. The majority of missense variants are regarded as benign / likely benign or VUS in ClinVar / LOVD.
Evidence considered
  • CSPEC PP2 entry: applicability is Not applicable.
  • APC_specifications_supplementary-material_V2.pdf, PP2 row: missense variants are not a frequent mutation type in APC; the majority are regarded as benign, likely benign, or VUS in ClinVar / LOVD.
  • No exact variant row was found when searching c.3920T>A, p.Ile1307Lys, and p.I1307K in the governing APC supplementary file.
Still missing
  • No exact c.3920T>A, p.Ile1307Lys, or p.I1307K entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PP4 VCEPNot applicable: the APC VCEP states that PP4 is already captured by PS4 and cannot provide independent evidence. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that PP4 is already captured by PS4 specifications and cannot be used as independent evidence.

VCEP rule
Already captured by the specifications of PS4, and thus cannot be used as independent evidence.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PP4 row: the VCEP says PP4 is already captured by PS4 and cannot be used as independent evidence.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗
PP5 VCEPNot applicable: the APC VCEP says PP5 is not used because expert opinions require the accompanying primary evidence for independent evaluation. Details ▾Hide ▴
Reasoning

The APC VCEP marks PP5 as not used and states that expert opinions should only be considered when accompanied by the primary evidence used.

VCEP rule
Not used as recommended by Biesecker et al. 2018 (PMID: 29543229): Expert opinions should only be considered if accompanied by the primary evidence used.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PP5 row: the VCEP states PP5 is not used as recommended by Biesecker et al. 2018 (PMID:29543229).
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗
BP3 VCEPNot applicable: the APC VCEP explicitly does not use BP3 due to limited available data, and this variant is a missense SNV rather than an in-frame indel. Details ▾Hide ▴
Reasoning

BP3 is not applicable because the APC VCEP explicitly states that BP3 is not used due to limited available data. The variant is also a missense SNV rather than an in-frame deletion or insertion in a repeat region.

VCEP rule
APC VCEP: Not used due to limited available data.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, BP3 row: 'APC VCEP: Not used due to limited available data.'
  • Variant-level assessment: the consequence is missense and the variant is not an in-frame insertion or deletion.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗pvs1_variant_assessment
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI score of 0.00. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP4 is not applicable to missense variants. This variant is a missense change, so BP4 is not applicable upstream of evaluating any no-impact splice prediction. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
**Missense variants:** BP4 is not applicable.
Evidence considered
  • ClinGen APC CSPEC BP4 rule: BP4 is not applicable for missense variants; the no-impact splice-prediction path is limited to synonymous or intronic variants.
  • APC_specifications_supplementary-material_V2.pdf, BP4 row: BP4 is not applicable for missense variants.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP6 VCEPNot applicable: the APC VCEP explicitly prohibits use of BP6 for this VCEP. Details ▾Hide ▴
Reasoning

The APC VCEP marks BP6 as not applicable for this VCEP and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, BP6 row: the VCEP says BP6 is not used as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗cspec ↗
BP7 N/ANot applicable: BP7 covers synonymous or qualifying intronic variants, whereas c.3920T>A is a missense exonic variant. Details ▾Hide ▴
Reasoning

The APC VCEP BP7 rule is limited to synonymous variants or intronic variants at or beyond +7/-21. This variant is a missense exonic variant at c.3920T>A in exon 16, so BP7 is outside its governing scope. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
A synonymous (silent) or intronic variant at or beyond +7/−21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
  • ClinGen APC CSPEC BP7 rule: BP7 applies to synonymous or intronic variants at or beyond +7/-21 with multiple splice predictors showing no impact to the splice consensus or creation of a new splice site.
  • APC variant facts: NM_000038.6:c.3920T>A is a missense variant in exon 16, encoding NP_000029.2:p.(Ile1307Lys).
  • APC_specifications_supplementary-material_V2.pdf, BP7 row: the APC rule does not require a conservation prediction for synonymous and intronic variants, but retains the synonymous/intronic scope.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Identifiers

Gene
APC
Transcript
NM_000038.6
Coding (HGVS c.)
NM_000038.6:c.3920T>A
Protein (HGVS p.)
NP_000029.2:p.(Ile1307Lys)
GRCh38
chr5:112839514 T>A
GRCh37
chr5:112175211 T>A
Location and type
Exon 16 · missense
ClinVar
822
COSMIC
COSV57326270

Gene diagram

Every interpreted variant in APC, mapped onto the exon structure of NM_000038.6. Select a row to find it on the plot.

APCNM_000038.6
Fetching transcript structure from UCSC…
gnomAD v4.1 2,000 / 1,614,038 alleles AF 0.00124 · 29 homozygotes · FAF 0.0186
gnomAD v2.1 524 / 282,418 alleles AF 0.00186 · 7 homozygotes · FAF 0.000565
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0012 · 2000 / 1,614,038 alleles · 29 hom · FAF 0.019
Ashkenazi Jewish1089 / 29,608 0.03723 hom
Middle Eastern131 / 6,062 0.0225 hom
Remaining individuals208 / 62,510 0.00331 hom
Admixed American35 / 59,992 0.00058
South Asian48 / 91,066 0.00053
European (non-Finnish)480 / 1,179,986 0.00041
African/African American9 / 75,006 0.00012
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, East Asian.

gnomAD v2.1

AF 0.0019 · 524 / 282,418 alleles · 7 hom · FAF 0.00056
Ashkenazi Jewish375 / 10,358 0.0367 hom
Remaining individuals22 / 7,204 0.0031
South Asian22 / 30,616 0.00072
European (non-Finnish)82 / 128,840 0.00064
Admixed American22 / 35,416 0.00062
African/African American1 / 24,934 4e-05
0 alternate alleles recorded in 2 other groups: East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00123913; MAF= 0.12391%, 2000/1614038 alleles, homozygotes = 29) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0367806; MAF= 3.67806%, 1089/29608 alleles, homozygotes = 23); grpmax FAF= 0.0186005.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00185541; MAF= 0.18554%, 524/282418 alleles, homozygotes = 7) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0362039; MAF= 3.62039%, 375/10358 alleles, homozygotes = 7); grpmax FAF= 0.00056452.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.002985884907709012, 55/18420 alleles, homozygotes = 1).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -363 bp
0.000
SpliceAI acceptor gainat -72 bp
0.000
SpliceAI donor lossat +319 bp
0.000
SpliceAI donor gainat +21 bp
0.000
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.001

Other predictors

REVEL
0.233
BayesDel
-0.206

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta score is 0.00, indicating no significant splice impact for this missense variant under the APC VCEP PP3 path. Details ▾Hide ▴
Reasoning

The APC VCEP PP3 rule excludes conservation and evolutionary models for missense variants and directs use of in silico splicing predictors to reveal possible splicing effects. This variant is a missense change, and the governing evidence reports SpliceAI DS_AG, DS_AL, DS_DG, and DS_DL values of 0.00, with a maximum delta score of 0.00 and no significant splice impact. Therefore, the named computational path does not support a deleterious splicing effect and PP3 is not met. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects.
Evidence considered
  • ClinGen APC CSPEC PP3 missense rule: do not use conservation or evolutionary computational models; use in silico splicing predictors for presumed missense variants to reveal possible splicing effects.
  • APC_specifications_supplementary-material_V2.pdf, PP3 row: the APC VCEP excludes computational prediction models for conservation/evolution in missense variants and lists SpliceAI among recommended splice prediction programs.
  • SpliceAI result for NM_000038.6:c.3920T>A / NP_000029.2:p.(Ile1307Lys): DS_AG=0.00, DS_AL=0.00, DS_DG=0.00, DS_DL=0.00; maximum delta score=0.00; reported as no significant splice impact.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗spliceai ↗
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI score of 0.00. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP4 is not applicable to missense variants. This variant is a missense change, so BP4 is not applicable upstream of evaluating any no-impact splice prediction. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
**Missense variants:** BP4 is not applicable.
Evidence considered
  • ClinGen APC CSPEC BP4 rule: BP4 is not applicable for missense variants; the no-impact splice-prediction path is limited to synonymous or intronic variants.
  • APC_specifications_supplementary-material_V2.pdf, BP4 row: BP4 is not applicable for missense variants.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP7 N/ANot applicable: BP7 covers synonymous or qualifying intronic variants, whereas c.3920T>A is a missense exonic variant. Details ▾Hide ▴
Reasoning

The APC VCEP BP7 rule is limited to synonymous variants or intronic variants at or beyond +7/-21. This variant is a missense exonic variant at c.3920T>A in exon 16, so BP7 is outside its governing scope. No exact-variant entry was found when searching APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, and p.I1307K.

VCEP rule
A synonymous (silent) or intronic variant at or beyond +7/−21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
  • ClinGen APC CSPEC BP7 rule: BP7 applies to synonymous or intronic variants at or beyond +7/-21 with multiple splice predictors showing no impact to the splice consensus or creation of a new splice site.
  • APC variant facts: NM_000038.6:c.3920T>A is a missense variant in exon 16, encoding NP_000029.2:p.(Ile1307Lys).
  • APC_specifications_supplementary-material_V2.pdf, BP7 row: the APC rule does not require a conservation prediction for synonymous and intronic variants, but retains the synonymous/intronic scope.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/APC/fulltext/APC_specifications_supplementary-material_V2.pdf.txt for c.3920T>A, p.Ile1307Lys, or p.I1307K.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.233. BayesDel score = -0.205789.

7 paper records listed. 1 cited in the classification.

Cited in the classification

  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene pred
    The study reported the exact APC I1307K variant and evaluated its protein function in a beta-catenin-regulated transcription assay. I1307K showed compromised function, with reduced ability to suppress transcription, rather than retention of wild-type activity.
    → PS3 · supporting Names this variant
    PMID 18199528 ↗
    Source detail
    Both I1307K and E1317Q were found to be functionally compromised.

    Location Results, 'Functional analyses of nonsynonymous variants in the β-catenin down-regulating domain'; Table 1

    Context Sequencing of APC in 691 North American patients with colorectal adenomas and 969 matched healthy controls; beta-catenin-regulated transcription luciferase assays in SW480 APC-deficient cells, averaged over at least 10 independent experiments.

Other recorded publications

  • The APC variants I1307K and E1317Q are associated with colorectal tumors, but no
    The paper explicitly studied APC c.3920T>A (I1307K) and identified three heterozygous carriers among patients with multiple colorectal adenomas; no family segregation or parental testing was reported.
    Names this variant
    PMID 9724771 ↗
    Quoted passage
    three individuals with the I1307K allele (as heterozygote with the ‘wild type’) were detected in Groups 1 and 2 while using the ARMS PCR (confirmed on sequencing).

    Results, paragraph beginning ‘An ARMS PCR was used to test for the I1307K variant’

  • Phenotypic characteristics associated with the APC gene I1307K mutation in Ashkenazi Jewish patients with colorectal polyps.
    Syngal S et al. · 2000
    In Ashkenazi Jewish patients with colorectal polyps but no colorectal cancer, APC I1307K occurred in 22 of 161 patients with adenomatous polyps and in 1 of 20 with hyperplastic polyps; parental testing, informative meioses, and affected noncarrier family members were not reported.
    Names this variant
    PMID 10938175 ↗
    Quoted passage
    The I1307K variant was identified in 22 (14%) of 161 Ashkenazi Jewish patients with a history of adenomatous polyps

    Abstract, Results; Results section, paragraph beginning ‘Carrier rates were determined’; Tables 2 and 3

  • APC I1307K increases risk of transition from polyp to colorectal carcinoma in Ashkenazi Jews.
    Stern HS et al. · 2001
    No paper-specific finding is recorded.
    PMID 11159880 ↗
  • Clinical and screening implications of the I1307K adenomatous polyposis coli gen
    Among 718 Israeli Jewish participants, I1307K was identified in 8.1% of European/Ashkenazi-origin participants and 1.2% of non-European-origin participants; among Ashkenazi participants with familial colorectal neoplasia, carrier frequency was 10.7% with reported relative risk 1.73 versus Ashkenazi controls, not statistically significant.
    Names this variant
    PMID 12173321 ↗
    Quoted passage
    Overall, the I1307K variant was identified in 40 individuals.

    Results, Ethnic Prevalence; Risk-Group Prevalence; Clinical Features; Tables 1 and 2

  • Colorectal polyps in carriers of the APC I1307K polymorphism.
    In 900 northern Israeli colorectal-cancer cases, 78 carried APC I1307K; carriers had more polyps in surgical specimens than noncarriers (reported age-adjusted comparisons), but this paper did not provide a matched carrier-frequency control comparison for the variant itself in the extracted evidence.
    Names this variant
    PMID 16228836 ↗
    Quoted passage
    APC I1307K carriers were significantly more likely than noncarriers to have any polyps in their surgical specimen after age-adjustment (51.3 percent vs. 33.6 percent, P = 0.03).

    Results, ‘Prevalence of Polyps’; Table 2

  • No evidence of the APC D1822V missense variant's pathogenicity in Tunisian patie
    The paper explicitly studied APC I1307K and detected it in one of 48 unrelated Tunisian sporadic colorectal-cancer patients; it provided no functional assay, segregation analysis, or detailed case-level phenotype.
    Names this variant
    PMID 18343606 ↗
    Quoted passage
    Out of 63 healthy individuals and 48 CRC cases, we find the I1307K variant in only one CRC patient.

    Results and discussion, paragraph 1

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

gnomAD v4.1 2,000 / 1,614,038 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 20 Uncertain significance · 8 Likely pathogenic · 7 risk factor · 5 Established risk allele · 4 Pathogenic · 1 association · 1 pathogenic · 1 Likely benign 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

This variant is present in gnomAD v4.1 (AF= 0.00123913; MAF= 0.12391%, 2000/1614038 alleles, homozygotes = 29) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0367806; MAF= 3.67806%, 1089/29608 alleles, homozygotes = 23); grpmax FAF= 0.0186005.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00185541; MAF= 0.18554%, 524/282418 alleles, homozygotes = 7) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0362039; MAF= 3.62039%, 375/10358 alleles, homozygotes = 7); grpmax FAF= 0.00056452.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.002985884907709012, 55/18420 alleles, homozygotes = 1).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (20 clinical laboratories) and as Likely pathogenic (8 clinical laboratories) and as risk factor (7 clinical laboratories) and as Established risk allele (5 clinical laboratories) and as Pathogenic (4 clinical laboratories) and as association (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 822)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.233. BayesDel score = -0.205789.

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 previously been reported in somatic cancers (COSMIC; COSV57326270, n = 23 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.