APC

Chr 5AD

APC regulator of Wnt signaling pathway

Also known as: BTPS2, DESMD, DP2, DP2.5, DP3, GS, PPP1R46

NCBI Gene: 324 ENSG00000134982 UniProt: P25054

This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

Primary Disease Associations & Inheritance

Adenoma, periampullary, somaticMIM #175100

Adenomatous polyposis coliMIM #175100

Brain tumor-polyposis syndrome 2MIM #175100

Colorectal cancer, somaticMIM #114500

Desmoid disease, hereditaryMIM #135290

Gardner syndromeMIM #175100

Gastric adenocarcinoma and proximal polyposis of the stomachMIM #619182

Gastric cancer, somaticMIM #613659

Hepatoblastoma, somaticMIM #114550

UniProtFamilial adenomatous polyposis 1

UniProtMedulloblastoma

UniProtHepatocellular carcinoma

500

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— APC

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Gene-Disease Validity (ClinGen)

gastric adenocarcinoma and proximal polyposis of the stomach · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

69 Pathogenic / Likely Pathogenic· 330 VUS of 500 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.16LOEUF

pLI 1.000

Z-score 8.90

OE 0.10 (0.06–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.17Z-score

OE missense 0.99 (0.94–1.03)

1436 obs / 1454.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.06–0.16)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.94–1.03)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11

0≤1.21.6

LoF obs/exp: 11 / 113.2Missense obs/exp: 1436 / 1454.0Syn Z: -1.98

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53

Likely Pathogenic16

VUS330

Likely Benign100

Conflicting1

Pathogenic

Likely Pathogenic

330

VUS

100

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	0	8	0	53
Likely Pathogenic	12	1	3	0	16
VUS	5	270	52	3	330
Likely Benign	0	0	11	89	100
Benign	0	0	0	0	0
Conflicting	—				1
Total	62	271	74	92	500

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

APC · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

APC-related adenomatous polyposis coli

definitive

ADLoss Of FunctionAbsent Gene Product

EyeSkinCancer

G2P ↗

APC-related desmoid disease, hereditary

definitive

ADUndeterminedUncertain

Skin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

APC REGULATOR OF WNT SIGNALING PATHWAY; APC

MIM #611731 · *

Adenoma, periampullary, somatic

MIM #175100