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APCc.4348C>TLikely pathogenic
Print report
Variant interpretation report

APC c.4348C>T, p.Arg1450Ter

NM_000038.6:c.4348C>T NP_000029.2:p.(Arg1450Ter) Nonsense · exon 16 View identifiers
Classification
Likely pathogenic

Variant description:

The APC NM_000038.6:c.4348C>T (NP_000029.2:p.(Arg1450Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV57321313, n = 737 times). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Likely Pathogenic.

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

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

Met, very strong: nonsense codon 1450 lies within the APC VCEP's codon 49–2645 interval assigned full PVS1.

PS4Supporting
PS4 · supporting

Met at Supporting: two unrelated FAP probands contribute 1.5 APC phenotype points, matching the VCEP 1–1.5-point Supporting threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: APC VCEP Rule20 is satisfied by PVS1 (very strong) plus PS4 (supporting), with no benign rule met.

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
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251172 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
10 reported laboratory submissions

10 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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
737 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57321313, n = 737 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: 2 met · 0 not met · 12 not assessed · 14 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

All four requested segregation/de novo criteria are not_assessed because the variant-specific reports provide affected probands but no parental testing, family segregation, meiosis counts, or affected noncarrier data.

The required APC VCEP files were searched under all three supplied variant notations; neither file contains a pre-assigned code for this variant.

PS4 is met at Supporting strength from 1.5 APC VCEP phenotype points contributed by two unrelated affected probands in PMID:26446593; PMID:21110124 provides an independent affected-versus-control observation but its corrected confidence interval includes 1.

PP4, PP5, and BP6 are not applicable because the APC VCEP explicitly excludes them as independent evidence or does not use them.

BP5 is not assessed because no qualifying alternate pathogenic adenomatous-polyposis gene variant is documented.

All three requested computational criteria are not_applicable because the variant is a coding nonsense change, outside the variant classes named by the APC VCEP PP3, BP4, and BP7 rules.

Met · 2

PVS1 Very strongVCEPMet, very strong: nonsense codon 1450 lies within the APC VCEP's codon 49–2645 interval assigned full PVS1. Details ▾Hide ▴
Reasoning

NM_000038.6:c.4348C>T is a nonsense variant producing NP_000029.2:p.(Arg1450Ter) / p.(R1450*) in coding exon 16. The APC VCEP PVS1 decision tree assigns nonsense or frameshift variants causing a premature truncation codon between codons 49 and 2645 to full PVS1; codon 1450 is within that interval. The VCEP states that APC loss of function is the predominant disease mechanism and that NMD is not essential for pathogenicity because truncating variants, especially in last exon 16, are well described. The exact variant was reported as a heterozygous nonsense change in exon 15 in two Korean FAP patients and as c.4348C>T/p.Arg1450* in two unrelated FAP probands; these reports corroborate the variant identity and truncating consequence but are not needed to invoke the VCEP decision-tree assignment.

VCEP rule
Nonsense or frameshift | Variants causing a frameshift or premature truncation codon between and including codon 49 and 2645 | PVS1 ... APC is a gene where LOF is the predominant mechanism of disease. ... Nevertheless, since truncating variants throughout the gene are well described, especially in the last exon 16 (which comprises 77% of the gene), NMD seems not to be essential for pathogenicity.
Evidence considered
  • Case consequence assessment: NM_000038.6:c.4348C>T is a nonsense variant, NP_000029.2:p.(Arg1450Ter) / p.(R1450*), in exon 16.
  • APC VCEP Figure 1 nonsense/frameshift row: variants causing a frameshift or premature truncation codon between and including codon 49 and 2645 are assigned PVS1.
  • APC VCEP supplementary PVS1 specification: APC is a gene where LOF is the predominant mechanism of disease; truncating variants are well described, especially in last exon 16, and NMD seems not to be essential for pathogenicity.
  • PMID:26446593, Results Table 1: HD001 and HFC213 were reported with c.4348C>T p.Arg1450*; both had classical FAP and more than 100 polyps.
  • PMID:21110124, Table 1 and Results: c.4348C>T/p.Arg1450X was reported as a heterozygous nonsense mutation in exon 15 in 2 of 23 unrelated Korean FAP patients.
Still missing
  • No exact entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt; the governing PVS1 rule was applied from its general nonsense-variant specification.
  • No exact entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf.txt; the figure's general nonsense/frameshift codon-range row governs this variant.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 ↗pvs1_variant_assessmentcspec ↗PMID:26446593 ↗PMID:21110124 ↗
PS4 SupportingVCEPMet at Supporting: two unrelated FAP probands contribute 1.5 APC phenotype points, matching the VCEP 1–1.5-point Supporting threshold. Details ▾Hide ▴
Reasoning

The APC VCEP PS4 rule requires increased prevalence in affected individuals versus controls and assigns strength from APC phenotype points. The exact variant was reported in two unrelated Hungarian FAP probands in PMID:26446593: HD001, age 19, with more than 100 polyps and classical FAP/Gardner syndrome, and HFC213, age 42, with more than 100 polyps and classical FAP. Under the VCEP Table 1, the age-19 proband scores 1 phenotype point (≥100 adenomas at ≤30 years) and the age-42 proband scores 0.5 point (≥20 adenomas at age 20–70 years), for 1.5 total points; the VCEP PS4 strength rule for 1–1.5 points is Supporting. PMID:21110124 independently reports the exact variant in 2 of 23 Korean FAP patients (2/46 alleles) and 0 of 50 healthy Korean controls (0/100 alleles). The raw case-control odds ratio is unbounded because the control cell is zero; with a Haldane correction, OR=11.29 and 95% CI=0.53–240.08, so the corrected interval includes 1 and the VCEP case-control OR/CI route is not independently decisive. The PS4 call therefore rests on the VCEP phenotype-point route, with the independent affected-versus-control observation as supporting context. Neither governing VCEP file contains a pre-assigned row for c.4348C>T, p.Arg1450Ter, or p.R1450*.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls ... 1-1.5 phenotype point.
Evidence considered
  • PMID:26446593, Results Table 1, rows HD001 and HFC213: both carry c.4348C>T p.Arg1450*, both have >100 polyps and classical FAP; HD001 was diagnosed at 19 years and HFC213 at 42 years.
  • VCEP Table 1: ≥100 colorectal adenomas at ≤30 years scores 1 point; ≥20 colorectal adenomas at age 20–70 years scores 0.5 point. The two PMID:26446593 probands therefore score 1.5 total points.
  • VCEP CSPEC PS4 strength rule: 1–1.5 phenotype point corresponds to Supporting evidence.
  • PMID:21110124 Table 1: c.4348C>T p.Arg1450X occurred in 2 heterozygous patient alleles among 46 patient alleles and was absent from 100 control alleles; Haldane-corrected OR=11.29, 95% CI=0.53–240.08, calculated from the reported counts.
  • The requested searches of APC_specifications_supplementary-material_V2.pdf.txt and Table-1%262.pdf.txt found no exact-variant entry under c.4348C>T, p.Arg1450Ter, or p.R1450*.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in Table-1%262.pdf.txt.
  • The case-control comparison has zero controls with the variant; the Haldane-corrected 95% CI includes 1, so a finite statistically significant OR/CI was not established.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:26446593 ↗PMID:21110124 ↗

Not assessed · 12 · no assessment recorded

PS2 VCEPNot assessed: two affected probands are reported, but no parental testing or de novo determination is available to assign the VCEP's 1- or 2-point score. Details ▾Hide ▴
Reasoning

The APC VCEP requires de novo status with confirmed maternity and paternity, disease in the patient, and no family history; its scoring table assigns 2 points per proband with confirmed parental relationships or 1 point when parental relationships are unconfirmed, provided the phenotype reaches at least 1 point. PMID:26446593 reports two unrelated probands with c.4348C>T/p.Arg1450* and classical FAP, including more than 100 polyps, but provides no parental testing, parental phenotype, de novo determination, or family-history assessment. PMID:21110124 reports the variant in two unrelated Korean FAP patients but likewise provides no variant-specific parental or de novo evidence. Therefore the VCEP PS2 score cannot be evaluated.

VCEP rule
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history ... The parents should have been colonoscoped, less than five colorectal adenomas in a colonoscopy and no other phenotypic conspicuities from Table 1 are regarded as inconspicuous. ... ≥ 1 ... 2 ... 1
Evidence considered
  • PMID:26446593, Results Table 1, rows HD001 and HFC213: c.4348C>T p.Arg1450* was reported in two unrelated probands with more than 100 polyps and classical FAP; the paper does not report parental testing, de novo status, or family history for these variant observations.
  • PMID:21110124, Table 1 and Results: p.Arg1450X, equivalent to p.Arg1450Ter, was reported among mutations in two of 23 unrelated Korean FAP patients; no variant-specific parental or de novo evidence was reported.
  • Table-1%262.pdf, Table 1 and Table 2: phenotype points and de novo scores require phenotype classification plus confirmed or unconfirmed parental relationships; the available reports do not provide the parental information needed to assign a score.
Still missing
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in Table-1%262.pdf.txt.
  • Parental genotypes, maternity and paternity confirmation, parental phenotype assessment, and family history are not reported for the variant-specific probands.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:26446593 ↗PMID:21110124 ↗
PS3 VCEPNot assessed: no exact-variant RNA or qualifying protein assay result is available to meet the APC VCEP PS3 functional-study requirements. Details ▾Hide ▴
Reasoning

The APC VCEP permits PS3 when an RNA assay demonstrates the specified premature-stop or exon-skipping consequence with the required full-length-transcript result, or when a qualifying protein assay demonstrates increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding by surface plasmon resonance. The case materials contain no exact-variant RNA or protein assay result for NM_000038.6:c.4348C>T (p.Arg1450Ter/p.R1450*), and the governing APC supplementary file contains no entry for c.4348C>T, p.Arg1450Ter, or p.R1450*. Therefore PS3 cannot be assigned at any strength from the available evidence.

VCEP rule
**RNA assays** show 1. inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides **OR** 2. over-expression of an alternative transcript (exons 10, 11 or 15) **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
  • ClinGen InSiGHT APC CSPEC PS3 entry: RNA assays must show the specified premature-stop or exon-skipping consequence with the required full-length-transcript result; the supporting path also permits qualifying protein assays showing increased beta-catenin regulated transcription activity and/or decreased beta-catenin binding by surface plasmon resonance.
  • APC_specifications_supplementary-material_V2.pdf.txt, PS3 section: the VCEP specifies demonstrating absence of full-length transcript or less than 10% full-length transcript and demonstrating overexpression of an alternative transcript where applicable; no row for c.4348C>T, p.Arg1450Ter, or p.R1450* was present.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • An exact-variant RNA assay result demonstrating the VCEP-specified transcript consequence and full-length-transcript proportion is unavailable.
  • An exact-variant qualifying protein assay result measuring beta-catenin-regulated transcription activity and/or beta-catenin binding by surface plasmon resonance is unavailable.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM2 VCEPNot assessed: VCEP-required non-cancer gnomAD allele count and frequency are unknown because the query failed. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PM2_Supporting using the non-cancer gnomAD v2.1.1 total population and defines rarity as allele frequency ≤ 0.0003% when allele count is >1 or <0.001% when allele count is ≤1. The case evidence reports that the gnomAD v2.1 non-cancer query failed and its frequency is unknown; therefore allele count and frequency cannot be evaluated under the VCEP rule. Searches of APC_specifications_supplementary-material_V2.pdf.txt for c.4348C>T, p.Arg1450Ter, and p.R1450* found no variant-specific entry.

VCEP rule
The allele frequency ≤ 0.0003% (0.000003) is used if the allele count is > 1. To tolerate the occurrence 1 x in gnomAD the VCEP has set an allele frequency < 0.001% (0.00001) (which is below BS1) if the allele count is ≤ 1. ... In general, we recommend to use the total population from the non-cancer dataset from gnomAD (v2.1.1) or other large population datasets to determine allele frequency.
Evidence considered
  • APC VCEP supplementary specification, PM2: allele frequency ≤ 0.0003% (0.000003) if allele count is >1, or <0.001% (0.00001) if allele count is ≤1; the VCEP recommends the total population from the non-cancer gnomAD v2.1.1 dataset.
  • Case evidence: GNOMAD_V2_1_NON_CANCER query failed; frequency is UNKNOWN, not absent.
  • All-comers gnomAD v2.1 was 0/251172 alleles, AF 0, homozygotes 0, but it cannot substitute for the VCEP-required non-cancer result.
Still missing
  • The variant was not found in APC_specifications_supplementary-material_V2.pdf.txt under c.4348C>T, p.Arg1450Ter, or p.R1450*.
  • The required non-cancer gnomAD v2.1 allele count and frequency are unavailable because the query failed.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
PM6 VCEPNot assessed: affected probands are reported, but neither source documents assumed de novo status or the parental information required for the VCEP PM6 score. Details ▾Hide ▴
Reasoning

The APC VCEP PM6 pathway concerns an assumed de novo variant without confirmed maternity and paternity and uses the same phenotype and parental-relationship scoring tables as PS2. PMID:26446593 reports two unrelated affected probands with c.4348C>T/p.Arg1450*, and PMID:21110124 reports p.Arg1450X in two unrelated Korean FAP patients, but neither source documents an assumed de novo event, parental testing, parental phenotype, or family history. The required VCEP de novo score therefore cannot be assigned.

VCEP rule
Assumed de novo, but without confirmation of paternity and maternity ... The parents should have been colonoscoped, less than five colorectal adenomas in a colonoscopy and no other phenotypic conspicuities from Table 1 are regarded as inconspicuous. ... ≥ 1 ... 2 ... 1
Evidence considered
  • PMID:26446593, Results Table 1, rows HD001 and HFC213: two unrelated probands with c.4348C>T p.Arg1450* and classical FAP are reported, without parental or de novo information.
  • PMID:21110124, Table 1 and Results: p.Arg1450X is listed in two unrelated Korean FAP patients, without an assumed de novo interpretation or parental testing data.
  • Table-1%262.pdf, Table 2: a phenotype point of ≥1 yields a de novo score of 2 with confirmed parental relationships or 1 with unconfirmed relationships, but the case reports do not establish either relationship category.
Still missing
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in Table-1%262.pdf.txt.
  • No assumed de novo designation, parental genotypes, parental phenotype assessment, or family history is reported for the variant-specific cases.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:26446593 ↗PMID:21110124 ↗
PP1 VCEPNot assessed: no affected relatives with matching genotypes or segregation data are reported, so the VCEP's minimum 3-meiosis threshold cannot be evaluated. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PP1 strength from the number of segregating meioses: 3-4 for Supporting, 5-6 for Moderate, and at least 7 in at least 2 families for Strong. The VCEP counts only genotype- and phenotype-positive individuals and obligate carriers with phenotype. The available variant reports describe unrelated probands, not affected relatives with genotypes, and provide no segregation analysis or meiosis count. PP1 cannot therefore be evaluated.

VCEP rule
Variant segregates in ≥ 7 meioses in ≥ 2 families. ... Variant segregates in 5-6 meioses in ≥ 1 family. ... Variant segregates in 3-4 meioses in ≥ 1 family. ... Only genotype and phenotype positive individuals and obligate carriers with phenotype are counted
Evidence considered
  • PMID:26446593, Results Table 1: the variant is reported in two unrelated probands, HD001 and HFC213; no familial segregation or affected-relative genotypes are reported.
  • PMID:21110124, Results: the variant is reported in unrelated Korean FAP patients; no family segregation or meioses are reported.
  • APC_specifications_supplementary-material_V2.pdf, PP1 section: only genotype- and phenotype-positive individuals and obligate carriers with phenotype are counted, with relatives having ≥10 or multiple colorectal adenomas considered 0.5 point.
Still missing
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in Table-1%262.pdf.txt.
  • No affected relatives, carrier statuses, obligate-carrier phenotypes, family count, or meiosis count is available for this variant.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:26446593 ↗PMID:21110124 ↗
BA1 VCEPNot assessed: the VCEP-required non-cancer gnomAD v2.1 Popmax frequency is unknown because that query failed. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BA1 as allele frequency ≥ 0.1%, preferably using the Popmax Filtering Allele Frequency of the non-cancer gnomAD v2.1.1 dataset. The case evidence reports that the gnomAD v2.1 non-cancer query failed and its frequency is unknown; therefore the required population source is unavailable. The all-comers gnomAD v2.1 result (0/251172 alleles; AF 0) and gnomAD v4.1 absence cannot replace the VCEP-preferred non-cancer dataset for this assessment. Searches of APC_specifications_supplementary-material_V2.pdf.txt for c.4348C>T, p.Arg1450Ter, and p.R1450* found no variant-specific entry.

VCEP rule
Allele frequency ≥ 0.1% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))
Evidence considered
  • APC VCEP supplementary specification, BA1: ‘Allele frequency ≥ 0.1% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))’.
  • Case evidence: GNOMAD_V2_1_NON_CANCER query failed; frequency is UNKNOWN, not absent.
  • All-comers gnomAD v2.1 was 0/251172 alleles, AF 0, homozygotes 0, but this is not the VCEP-specified non-cancer dataset.
Still missing
  • The variant was not found in APC_specifications_supplementary-material_V2.pdf.txt under c.4348C>T, p.Arg1450Ter, or p.R1450*.
  • The required gnomAD v2.1 non-cancer Popmax Filtering Allele Frequency is unavailable because the query failed.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS1 VCEPNot assessed: the VCEP-required non-cancer gnomAD v2.1 Popmax frequency is unknown, so the 0.001% BS1 threshold cannot be evaluated. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS1 as allele frequency ≥ 0.001%, preferably using the Popmax Filtering Allele Frequency of the non-cancer gnomAD v2.1.1 dataset. The case evidence reports that the gnomAD v2.1 non-cancer query failed and its frequency is unknown; therefore the required population source is unavailable. The all-comers gnomAD v2.1 result (0/251172 alleles; AF 0) and gnomAD v4.1 absence cannot replace the VCEP-preferred non-cancer dataset for this assessment. Searches of APC_specifications_supplementary-material_V2.pdf.txt for c.4348C>T, p.Arg1450Ter, and p.R1450* found no variant-specific entry.

VCEP rule
Allele frequency ≥ 0.001% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))
Evidence considered
  • APC VCEP supplementary specification, BS1: ‘Allele frequency ≥ 0.001% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))’.
  • Case evidence: GNOMAD_V2_1_NON_CANCER query failed; frequency is UNKNOWN, not absent.
  • All-comers gnomAD v2.1 was 0/251172 alleles, AF 0, homozygotes 0, but this is not the VCEP-specified non-cancer dataset.
Still missing
  • The variant was not found in APC_specifications_supplementary-material_V2.pdf.txt under c.4348C>T, p.Arg1450Ter, or p.R1450*.
  • The required gnomAD v2.1 non-cancer Popmax Filtering Allele Frequency is unavailable because the query failed.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS2 VCEPNot assessed: VCEP-relevant non-cancer gnomAD homozygote data are unavailable because the query failed. Details ▾Hide ▴
Reasoning

The APC VCEP states that the non-cancer gnomAD v2.1.1 dataset may be used to search for homozygous individuals, while it cannot be used for heterozygous healthy individuals because phenotype information is limited. The case evidence reports that the gnomAD v2.1 non-cancer query failed, so the VCEP-relevant homozygote count is unavailable. Searches of APC_specifications_supplementary-material_V2.pdf.txt for c.4348C>T, p.Arg1450Ter, and p.R1450* found no variant-specific entry.

VCEP rule
The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.
Evidence considered
  • APC VCEP supplementary specification, BS2: ‘The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.’
  • Case evidence: GNOMAD_V2_1_NON_CANCER query failed; frequency is UNKNOWN, not absent.
  • The all-comers gnomAD v2.1 record reports homozygotes 0, but it does not establish the VCEP-required non-cancer homozygote result.
Still missing
  • The variant was not found in APC_specifications_supplementary-material_V2.pdf.txt under c.4348C>T, p.Arg1450Ter, or p.R1450*.
  • The required non-cancer gnomAD homozygote count is unavailable because the query failed.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS3 VCEPNot assessed: no exact-variant assay demonstrates preserved APC function, comparable beta-catenin activity, or absence of mRNA aberration under the VCEP BS3 requirements. Details ▾Hide ▴
Reasoning

The APC VCEP permits BS3 for an RNA assay of a synonymous or intronic variant showing no mRNA aberration with the specified expression or nonsense-mediated-decay controls, or for a protein assay showing retention of beta-catenin-regulated transcription activity comparable to wild type within the beta-catenin binding domain. This variant is a nonsense variant at codon 1450, and the case materials contain no exact-variant assay demonstrating preserved function or absence of splicing impact. The governing APC supplementary file contains no entry for c.4348C>T, p.Arg1450Ter, or p.R1450*. Therefore BS3 cannot be assigned.

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
  • ClinGen InSiGHT APC CSPEC BS3 entry: the supporting path requires an RNA assay showing no mRNA aberration without the stronger control requirements, or a protein assay showing retention of beta-catenin regulated transcription activity comparable to wild type for variants in APC codons 959-2129.
  • APC_specifications_supplementary-material_V2.pdf.txt, BS3 section: the original VCEP criterion is well-established functional studies showing no damaging effect on protein function or splicing, with no additional comment and no row for c.4348C>T, p.Arg1450Ter, or p.R1450*.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No exact-variant protein assay demonstrates beta-catenin-regulated transcription activity comparable to wild type.
  • No exact-variant RNA assay demonstrates no mRNA aberration with the VCEP-required control evidence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BS4 VCEPNot assessed: no affected noncarrier is documented, so the VCEP's 0.5-point minimum for BS4 Supporting cannot be evaluated. Details ▾Hide ▴
Reasoning

The APC VCEP requires an affected member without the variant scoring at least 1 phenotype point for BS4 Strong, or at least 0.5 phenotype points for BS4 Supporting; two affected noncarriers each scoring at least 0.5 points also satisfy Strong. The available literature reports affected variant carriers or does not provide family genotypes, and contains no affected family member documented without c.4348C>T/p.Arg1450*. Thus non-segregation cannot be evaluated.

VCEP rule
Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see Table 1). ... Affected member without the variant must score at least 0.5 phenotype points (see Table 1).
Evidence considered
  • PMID:26446593, Results Table 1: both listed individuals carrying c.4348C>T p.Arg1450* are affected probands; no affected noncarrier is reported.
  • PMID:21110124, Results: affected FAP patients with p.Arg1450X are reported, but no affected noncarrier or family genotype comparison is reported.
  • Table-1%262.pdf, Table 1: phenotype points are assigned per proband, but no affected noncarrier phenotype and genotype are available for the BS4 comparison.
Still missing
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.4348C>T, p.Arg1450Ter, or p.R1450* entry was found in Table-1%262.pdf.txt.
  • No affected family member without the variant, genotype result, or phenotype-point assessment is reported.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:26446593 ↗PMID:21110124 ↗
BP2 VCEPNot assessed: two reports lack documented trans phase, or at least three unknown-phase occurrences with different pathogenic APC variants, required by the VCEP. Details ▾Hide ▴
Reasoning

The APC VCEP permits BP2 at Supporting strength when the variant is observed in trans with a (Likely) Pathogenic APC variant, or at least three times with different (Likely) Pathogenic APC variants in unknown phase. PMID:26446593 reports c.4348C>T/p.Arg1450* in two probands but does not report a second pathogenic APC variant or phase, and PMID:21110124 reports c.4348C>T/p.Arg1450X as heterozygous in two patients without variant-specific phase or co-occurrence data. Thus the available evidence does not establish either VCEP BP2 pathway.

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 CSPEC BP2 entry: Supporting requires observation in trans with a (Likely) Pathogenic APC variant or at least three occurrences in unknown phase with different (Likely) Pathogenic APC variants.
  • Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary, Table 1, rows HD001 and HFC213: c.4348C>T p.Arg1450* was reported in two probands; no second APC variant or phase is reported for these observations.
  • Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype, Table 1 and Results: c.4348C>T/p.Arg1450X was reported as heterozygous in two patients; no variant-specific phase or pathogenic APC co-occurrence is reported.
Still missing
  • No affected-proband record documents c.4348C>T in trans with a (Likely) Pathogenic APC variant.
  • No evidence documents at least three occurrences with different (Likely) Pathogenic APC variants in unknown phase.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗PMID:26446593 ↗PMID:21110124 ↗
BP5 VCEPNot assessed: no alternate pathogenic adenomatous-polyposis gene variant is documented for the required colorectal polyposis phenotype. Details ▾Hide ▴
Reasoning

The APC VCEP BP5 rule is restricted to a colorectal polyposis phenotype with a (Likely) Pathogenic variant in another specified adenomatous polyposis gene. The available evidence documents APC-associated FAP for this variant but does not establish an alternate pathogenic POLD1, POLE, MUTYH, NTHL1, MSH3, MLH1, MSH2, MSH6, or PMS2 variant in the same case; therefore the rule cannot be evaluated.

VCEP rule
Can be used, if a (Likely) Pathogenic variant in another adenomatous polyposis gene was identified (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_specifications_supplementary-material_V2.pdf.txt, BP5 section: qualifying alternate genes are POLD1, POLE, MUTYH, NTHL1, MSH3, and in childhood/adolescent onset MLH1, MSH2, MSH6, or PMS2; colorectal polyposis must be present.
  • The available case evidence reports APC c.4348C>T p.Arg1450Ter in FAP probands but does not report a qualifying alternate-gene pathogenic variant.
Still missing
  • No qualifying alternate-gene pathogenic variant is documented in the available case evidence.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the APC VCEP limits PS1 to missense or splice variants, whereas c.4348C>T produces the nonsense change p.Arg1450Ter. Details ▾Hide ▴
Reasoning

The APC VCEP limits PS1 to missense and splice variants. NM_000038.6:c.4348C>T is a nonsense variant, p.(Arg1450Ter), so it is outside the criterion's specified variant types. The APC supplementary file had no entry for c.4348C>T, p.Arg1450Ter, or p.R1450*.

VCEP rule
This criterion can be applied to both missense and splice variants in _APC_.
Evidence considered
  • APC VCEP PS1 rule: the criterion can be applied to both missense and splice variants in APC; the case variant is nonsense, p.(Arg1450Ter).
  • APC_specifications_supplementary-material_V2.pdf: searches for c.4348C>T, p.Arg1450Ter, and p.R1450* returned no variant-specific entry.
  • Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary, Table 1: c.4348C>T p.Arg1450* was reported in two probands.
  • Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype: c.4348C>T was reported as the nonsense variant p.Arg1450X.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗PMID:26446593 ↗PMID:21110124 ↗
PM1 VCEPNot applicable: the APC VCEP marks PM1 Not Applicable and identifies no approved APC pathogenic missense hotspot or critical-domain route for residue 1450. Details ▾Hide ▴
Reasoning

The APC VCEP marks PM1 Not Applicable and states that APC has no established pathogenic missense hotspot; it also excludes somatic mutation-cluster data because most somatic variants are truncating. No authoritative domain_tables entry exists for APC, and residue 1450 therefore cannot create a PM1 route outside the VCEP rule.

VCEP rule
Not Applicable
Evidence considered
  • APC VCEP CSPEC entry for PM1: applicability is Not Applicable.
  • APC_specifications_supplementary-material_V2.pdf, PM1: only positions 1026 and 1028 are discussed as reported likely pathogenic missense positions; there is not enough evidence to define a mutational hotspot, and no other known pathogenic missense germline hotspots are identified.
  • APC_specifications_supplementary-material_V2.pdf, PM1: somatic mutation-cluster data could not be used for APC because the vast majority of somatic variants are truncating.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • vcep_materials.json has no APC domain_tables entry.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PM3 VCEPNot applicable: the APC VCEP marks PM3 not applicable for familial adenomatous polyposis. Details ▾Hide ▴
Reasoning

The APC VCEP marks PM3 as not applicable. The VCEP supplementary specification states that PM3 is not used for familial adenomatous polyposis because FAP has autosomal dominant inheritance.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen InSiGHT APC CSPEC PM3 entry: applicability is Not Applicable.
  • APC_specifications_supplementary-material_V2.pdf, PM3 row: the VCEP states that PM3 is not used because FAP has an autosomal dominant inheritance.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM4 VCEPNot applicable: APC VCEP PM4 is not used, and this variant is nonsense rather than an in-frame or stop-loss change. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that PM4 is not used because of limited available data. The criterion's listed variant types are in-frame deletions/insertions in a non-repeat region or stop-loss variants; this variant is a nonsense premature-stop variant and does not meet those named types.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants ... Not used due to limited available data.
Evidence considered
  • APC VCEP PM4 row: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; APC VCEP: not used due to limited available data.
  • Case consequence assessment identifies NM_000038.6:c.4348C>T as a nonsense variant producing p.(Arg1450Ter), not an in-frame or stop-loss variant.
Still missing
  • No exact entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PM5 N/ANot applicable: PM5 is restricted by the APC VCEP to missense variants at positions 1026 or 1028, while this variant is nonsense at Arg1450. Details ▾Hide ▴
Reasoning

The APC VCEP restricts PM5 to missense variants at amino-acid positions 1026 and 1028, where APC-specific likely pathogenic missense variants are known. This variant is nonsense at Arg1450, outside both the required variant type and positions. The APC supplementary file had no entry for the three requested notations.

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
  • APC VCEP PM5 rule: the criterion can only be used for missense variants at amino-acid positions 1026 and 1028; the case variant is nonsense p.(Arg1450Ter).
  • APC_specifications_supplementary-material_V2.pdf: searches for c.4348C>T, p.Arg1450Ter, and p.R1450* returned no variant-specific entry.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PP2 VCEPNot applicable: the APC VCEP explicitly marks PP2 Not Applicable, and the case variant is a nonsense rather than missense variant. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly marks PP2 Not Applicable. Its supplementary comment also states that missense variants are not a frequent mutation type in APC and that most are benign, likely benign, or VUS; this nonsense variant is outside the criterion's missense scope.

VCEP rule
Not Applicable
Evidence considered
  • APC VCEP CSPEC entry for PP2: applicability is Not Applicable.
  • APC_specifications_supplementary-material_V2.pdf, PP2: missense variants are not a frequent mutation type in APC, and most are regarded as benign, likely benign, or VUS.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PP3 N/ANot applicable: c.4348C>T is a nonsense variant, while the APC PP3 rule names presumed-missense splicing effects and non-canonical splicing variants. Details ▾Hide ▴
Reasoning

The APC VCEP rule limits this computational criterion to splicing effects in presumed missense variants and to non-canonical splicing variants. NM_000038.6:c.4348C>T is a coding nonsense variant, NP_000029.2:p.(Arg1450Ter), not a presumed missense or non-canonical splicing variant; therefore PP3 is not applicable. No predictor score is used outside the rule's stated scope.

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. ... **Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.
Evidence considered
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP PP3 rule was applied before predictor review; its named situations are presumed missense variants evaluated for possible splicing effects and non-canonical splicing variants evaluated with multiple in silico splicing predictors.
  • Computational predictions were not counted because this nonsense variant is outside the APC VCEP PP3 applicability scope.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PP4 VCEPNot applicable: the APC VCEP states PP4 is already captured by PS4 and cannot be used as independent evidence. Details ▾Hide ▴
Reasoning

The APC VCEP marks PP4 as not applicable because phenotype specificity is already captured by its 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.txt, PP4 section: phenotype specificity is already captured by PS4 and cannot be used independently.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PP5 VCEPNot applicable: the APC VCEP does not use PP5 without the primary evidence underlying an expert opinion. Details ▾Hide ▴
Reasoning

The APC VCEP does not use PP5, stating 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.txt, PP5 section: the criterion is not used as recommended by Biesecker et al. 2018 because expert opinions should be accompanied by primary evidence.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BP1 N/ANot applicable: BP1 is a missense criterion, whereas c.4348C>T is a nonsense variant at codon 1450, outside the codon 1021-1035 exception. Details ▾Hide ▴
Reasoning

The APC VCEP BP1 rule is for missense variants in a gene where primarily truncating variants cause disease, with an exception for missense variants in codons 1021-1035. NM_000038.6:c.4348C>T is nonsense at codon 1450, so it is outside the specified missense variant type.

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
  • APC VCEP BP1 rule: BP1 is applicable to APC except for missense variants located in the first 15-amino-acid repeat of the beta-catenin binding domain, codons 1021-1035.
  • Case normalization: NM_000038.6:c.4348C>T produces NP_000029.2:p.(Arg1450Ter), a nonsense variant at codon 1450.
  • APC_specifications_supplementary-material_V2.pdf: searches for c.4348C>T, p.Arg1450Ter, and p.R1450* returned no variant-specific entry.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BP3 VCEPNot applicable: APC VCEP BP3 is not used, and the variant is a nonsense substitution rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP3 is not used due to limited available data. In addition, the original BP3 concept concerns in-frame deletions/insertions in a repetitive region without a known function, whereas this variant is a nonsense substitution.

VCEP rule
APC VCEP: Not used due to limited available data.
Evidence considered
  • APC VCEP BP3 row: BP3 is not used due to limited available data; the original criterion concerns in-frame deletions/insertions in a repetitive region without a known function.
  • Case consequence assessment identifies NM_000038.6:c.4348C>T as a nonsense substitution producing p.(Arg1450Ter).
Still missing
  • No exact entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BP4 N/ANot applicable: c.4348C>T is a nonsense variant, whereas APC BP4 addresses synonymous or intronic variants with multiple no-impact splice predictions. Details ▾Hide ▴
Reasoning

The APC VCEP BP4 rule covers synonymous or intronic variants for which multiple in silico splicing predictors suggest no impact, and explicitly excludes missense variants. NM_000038.6:c.4348C>T is a nonsense variant. BP4 is therefore not applicable: a no-splice-impact prediction cannot negate this variant's truncating protein consequence.

VCEP rule
**Missense variants:** BP4 is not applicable. ... **Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Evidence considered
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP BP4 rule requires the synonymous/intronic situation and multiple in silico splicing predictors suggesting no impact; the variant is outside that scope.
  • A no-splice-impact prediction was not used to support BP4 because the variant is truncating, consistent with the criterion's scope limitation.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP6 VCEPNot applicable: the APC VCEP does not use BP6 for unsupported benign expert opinions. Details ▾Hide ▴
Reasoning

The APC VCEP marks BP6 as not used, requiring expert opinions to be accompanied by the primary evidence used rather than applying BP6 as standalone evidence.

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.txt, BP6 section: not used as recommended by Biesecker et al. 2018 because expert opinions require the accompanying primary evidence.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BP7 N/ANot applicable: c.4348C>T is a coding nonsense variant, not the synonymous or intronic variant required by the APC BP7 rule. Details ▾Hide ▴
Reasoning

The APC VCEP BP7 rule applies to synonymous or intronic variants at or beyond +7/-21 with multiple algorithms predicting no splice impact and no new splice site. NM_000038.6:c.4348C>T is a coding nonsense variant, not synonymous or intronic, so BP7 is not applicable.

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
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP BP7 rule requires a synonymous or intronic variant at or beyond +7/-21; this coding nonsense variant does not meet that applicability condition.
  • Splicing predictor results were not used because BP7 is upstream not_applicable for this variant type.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Identifiers

Gene
APC
Transcript
NM_000038.6
Coding (HGVS c.)
NM_000038.6:c.4348C>T
Protein (HGVS p.)
NP_000029.2:p.(Arg1450Ter)
GRCh38
chr5:112839942 C>T
GRCh37
chr5:112175639 C>T
Location and type
Exon 16 · nonsense
ClinVar
834336, 482442, 194585, 184934, 135703
COSMIC
COSV57321313

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 Allele count data not recorded
gnomAD v2.1 0 / 251,172 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v2.1

AF 0 · 0 / 251,172 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251172 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -11 bp
0.000
SpliceAI acceptor gainat +167 bp
0.000
SpliceAI donor lossat -109 bp
0.000
SpliceAI donor gainat -2 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.036

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/ANot applicable: c.4348C>T is a nonsense variant, while the APC PP3 rule names presumed-missense splicing effects and non-canonical splicing variants. Details ▾Hide ▴
Reasoning

The APC VCEP rule limits this computational criterion to splicing effects in presumed missense variants and to non-canonical splicing variants. NM_000038.6:c.4348C>T is a coding nonsense variant, NP_000029.2:p.(Arg1450Ter), not a presumed missense or non-canonical splicing variant; therefore PP3 is not applicable. No predictor score is used outside the rule's stated scope.

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. ... **Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.
Evidence considered
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP PP3 rule was applied before predictor review; its named situations are presumed missense variants evaluated for possible splicing effects and non-canonical splicing variants evaluated with multiple in silico splicing predictors.
  • Computational predictions were not counted because this nonsense variant is outside the APC VCEP PP3 applicability scope.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP4 N/ANot applicable: c.4348C>T is a nonsense variant, whereas APC BP4 addresses synonymous or intronic variants with multiple no-impact splice predictions. Details ▾Hide ▴
Reasoning

The APC VCEP BP4 rule covers synonymous or intronic variants for which multiple in silico splicing predictors suggest no impact, and explicitly excludes missense variants. NM_000038.6:c.4348C>T is a nonsense variant. BP4 is therefore not applicable: a no-splice-impact prediction cannot negate this variant's truncating protein consequence.

VCEP rule
**Missense variants:** BP4 is not applicable. ... **Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Evidence considered
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP BP4 rule requires the synonymous/intronic situation and multiple in silico splicing predictors suggesting no impact; the variant is outside that scope.
  • A no-splice-impact prediction was not used to support BP4 because the variant is truncating, consistent with the criterion's scope limitation.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP7 N/ANot applicable: c.4348C>T is a coding nonsense variant, not the synonymous or intronic variant required by the APC BP7 rule. Details ▾Hide ▴
Reasoning

The APC VCEP BP7 rule applies to synonymous or intronic variants at or beyond +7/-21 with multiple algorithms predicting no splice impact and no new splice site. NM_000038.6:c.4348C>T is a coding nonsense variant, not synonymous or intronic, so BP7 is not applicable.

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
  • Variant consequence is nonsense: NM_000038.6:c.4348C>T encodes NP_000029.2:p.(Arg1450Ter) / p.(R1450*).
  • The APC VCEP BP7 rule requires a synonymous or intronic variant at or beyond +7/-21; this coding nonsense variant does not meet that applicability condition.
  • Splicing predictor results were not used because BP7 is upstream not_applicable for this variant type.
Still missing
  • No entry for c.4348C>T, p.Arg1450Ter, or p.R1450* was found when APC_specifications_supplementary-material_V2.pdf.txt was searched; this does not alter the criterion's upstream not_applicable scope.
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). BayesDel score = 0.66.

9 paper records listed. 2 cited in the classification.

Cited in the classification

  • Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype.
    Han SH et al. · 2011 Mar
    The paper reports APC c.4348C>T as p.Arg1450X, a heterozygous nonsense mutation in exon 15, identified in 2 of 23 unrelated Korean patients with familial adenomatous polyposis.
    → PVS1 · very strong → PS4 · supporting Names this variant
    PMID 21110124 ↗
    Source detail
    Apart from the frequent 1,309 mutation, eight other different mutations were detected in unrelated Korean FAP patients: p.Leu180TyrfsX5, p.Arg232X, p.Gly567X, p.Ser1275PhefsX13, p.Leu1280CysfsX8, p.Arg1450X, p.Gln1529X, and p.Thr1556AsnfsX3.

    Location Table 1; Results and discussion, paragraph beginning "Apart from the frequent 1,309 mutation"

    Context APC germline mutation screening in 23 unrelated Korean patients with FAP using DHPLC followed by direct sequencing; variants were confirmed by resequencing a second DNA sample, with 50 healthy Korean control DNAs analyzed.

  • Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.
    The paper explicitly reports APC c.4348C>T encoding p.Arg1450* in two unrelated probands, HD001 and HFC213, both with classical familial adenomatous polyposis and more than 100 polyps; HD001 also had Gardner syndrome.
    → PVS1 · very strong → PS4 · supporting Names this variant
    PMID 26446593 ↗
    Source detail
    HD001 19 +++ cFAP,G 15 c.4348C>T p.Arg1450*[59] HFC213 42 +++ cFAP 15 c.4348C>T p.Arg1450*[59]

    Location Results, Table 1, Pathogenic APC variants: substitutions and small indels

    Context Cohort of 87 unrelated probands with familial adenomatous polyposis evaluated by APC coding-region and splice-junction sequencing, with MLPA for copy-number abnormalities; the variant was reported in two probands.

Other recorded publications

  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.
    No paper-specific finding is recorded.
    PMID 18199528 ↗
  • Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract.
    No paper-specific finding is recorded.
    PMID 35849876 ↗
  • EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration.
    Wen Y et al. · 2004
    No paper-specific finding is recorded.
    PMID 15311282 ↗
  • Regulated binding of adenomatous polyposis coli protein to actin.
    Moseley JB et al. · 2007
    No paper-specific finding is recorded.
    PMID 17293347 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
    No paper-specific finding is recorded.
    PMID 23619274 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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 0.000 Open source ↗
ClinVar 10 Pathogenic 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

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251172 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories). (ClinVarID = 194585)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

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; COSV57321313, n = 737 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.