Classification rationale

PVS1PM2 Likely Pathogenic

APC c.1636C>T

NM_001127511.3:c.1636C>T (p.Arg546Ter) is a nonsense variant in APC, a gene where loss of function is the established mechanism for familial adenomatous polyposis.¹ This variant introduces a premature termination codon at position 546, upstream of the last exon-exon junction, predicting nonsense-mediated decay and complete loss of the C-terminal 2297 amino acids including all β-catenin binding and regulatory domains.² The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,730 alleles; AF=6.2×10⁻⁷), meeting PM2_Supporting under APC VCEP v2.1.0.³ ClinVar classifies this variant as Pathogenic based on submissions from multiple clinical laboratories, though individual case-level phenotype annotation is not publicly available for PS4 assessment.⁴ SpliceAI predicts no cryptic splice impact (max delta=0.01), consistent with this being a straightforward null variant rather than a splicing defect.⁵

PVS1 + PM2 → Likely Pathogenic

1 cspec ↗

2 pvs1_generic_framework ↗

3 gnomad_v2 ↗gnomad_v4 ↗

4 clinvar ↗

5 spliceai ↗

Gene diagram · NM_001127511.3 · variants mapped to exon structure

APC NM_001127511.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

1 / 1,613,730

6.2e-05%

Highest · European (non-Finnish)

8.5e-05%

Homozygotes

0

Allele frequency by ancestry — gnomAD v4.1

observed in 1 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	1 / 1,179,808	8.5e-05%	0
Admixed American	0 / 59,998	—	—
European (Finnish)	0 / 63,974	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,844	—	—
Middle Eastern	0 / 6,056	—	—
South Asian	0 / 91,058	—	—
Ashkenazi Jewish	0 / 29,596	—	—
African/African American	0 / 74,996	—	—

“

This variant is present in gnomAD v4.1 (AF= 6.19682e-07; MAF= 0.00006%, 1/1613730 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47596e-07; MAF= 0.00008%, 1/1179808 alleles, homozygotes = 0).

“

Absent from gnomAD v2.1.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 28 PMIDs triaged · 8 high-priority

28papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

11062151 ↗ functional

Expression of beta-catenin and full-length APC protein in normal and neoplastic colonic tissues.

Mutations of the APC gene are thought to be early events in the process of colorectal carcinogenesis. Although the complete function(s) of the APC gene product is not known, it has been shown that the APC protein interacts with beta-catenin in a multi-protein complex to regulate the level of expression of beta-catenin. Loss of normal APC protein function can lead to an accumulation of beta-catenin

BS3PM1PS3

11257105 ↗ functional

The ABC of APC.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the presence of adenomatous polyps in the colon and rectum, with inevitable development of colorectal cancer if left untreated. FAP is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Somatic mutations in the APC gene are an early event in colorectal tumorigenesis, and can be

BS3PM1PS3

15561772 ↗ functional

Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability.

The majority of human tumour cells are aneuploid owing to an underlying chromosome instability phenotype. While the genetic lesions that cause chromosome instability remain undefined, mouse ES cells harbouring homozygous adenomatous polyposis coli (APC) mutations are frequently tetraploid. In addition, colon cancer cells with APC mutations have weakened kinetochore-microtubule interactions. Furthe

BS3PM1PS3

1324223 ↗ functional

Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis.

Familial adenomatous polyposis (FAP) is a dominantly inherited condition predisposing to colorectal cancer. The recent isolation of the responsible gene (adenomatous polyposis coli or APC) has facilitated the search for germ line mutations in affected individuals. Previous authors have used the RNase protection assay and the single-strand conformation polymorphisms procedure to screen for mutation

BS3PP5PS3PS4

14523376 ↗ splicing rna

Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis.

A predominance of de novo mutations in the paternal germ line has been reported for several disorders; however, in familial adenomatous polyposis (FAP), the parental origin of APC mutations has been scarcely analysed so far. Among 563 unrelated FAP families with known family history, we identified 58 patients with a suspected de novo mutation in the APC gene. A germline mutation was detected in 52

BP7PP3PP5PS4PVS1

15833136 ↗ splicing rna

Rare mutations predisposing to familial adenomatous polyposis in Greek FAP patients.

Familial Adenomatous Polyposis (FAP) is caused by germline mutations in the APC (Adenomatous Polyposis Coli) gene. The vast majority of APC mutations are point mutations or small insertions/deletions which lead to truncated protein products. Splicing mutations or gross genomic rearrangements are less common inactivating events of the APC gene. In the current study genomic DNA or RNA from ten unrel

BP7PP3PP5PS4PVS1

23159591 ↗ splicing rna

APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests.

Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Con

BP7PP3PP5PS4PVS1

24033266 ↗ functional

A systematic approach to assessing the clinical significance of genetic variants.

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a s

BS3PS3PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PS3PS4

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots