APC

Gene Facts

• HGNC Symbol: APC (HGNC:583)
• HGNC Name: APC regulator of WNT signaling pathway
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: DP2, DP3, DP2.5, PPP1R46
• %HI: 2.19
• pLI: 1
• LOEUF: 0.32
• Cytoband: 5q22.2
• Genomic Coordinates:

  GRCh37/hg19:	chr5:112043195-112181936
  GRCh38/hg38:	chr5:112707498-112846239

• MANE Select Transcript: NM_000038.6 ENST00000257430.9
• Function: Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)- induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Associates with both microtubules and actin filaments, components of the cytoskeleton (PubMed:17293347). Plays a ro... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-9250
• ClinGen Curation ID: CCID:006674
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 07/19/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• familial adenomatous polyposis 1

HI Evidence

• PUBMED: 1651174
  The earliest reports were led by a US (Groden et al., PMID: 1651174) and Japanese group, Nagase et al (1992; n = 22 unrelated cases; PMID: 1319838), Miyoshi et al (1992; n = 53 familial cases; PMID: 1316610). This data reported germline variants in APC among patients with colorectal polyps in FAP or familial adenomatous polyposis patients. Most of these variants were predicted to cause truncation of the gene product by frameshift or a nonsense variant in APC.
• PUBMED: 10051640
  It was further described by Laken et al (PNAS; 1999) that ~80% of FAP patients can be shown to have truncating mutations of the APC gene. Seven of nine patients analyzed in there study were also found to have significantly reduced expression from one of the two allelic APC loci
• PUBMED: 23159591
  In Kerr et al., (JMD, 2012), one of the largest study of APC germline mutations (n = 1591 tests), reported large deletions / partial duplications as well as canonical splice site mutations as a significant cause of FAP.

• HI Evidence Comments: APC is one of the most frequently mutated driver genes in colorectal cancer with close to 100% penetrance (PMID: 28253712). It is also understood that FAP has varied phenotypic consequences, including Gardner and Turcot syndromes (PMID: 30855821). Of note, as of July 2021, 1839 variants are reported in Human gene mutation database (HGMD) public version (over 2000 in professional licensed version of HGMD as of July 2021). Gross deletions account for 130 variants (several with entire APC gene and 1 or 2 adjacent gene deletions reported). Further over 450 variants are reported as short variants (missense/nonsense in HGMD) with the majority being nonsense loss of function events. Additional recent studies (2018-2021) and large sequencing efforts in which pathogenic variants in APC have been described among patients with FAP or FAP-like disease. Some of these are detailed below: PMID: 30259713: describes the largest deletion of APC gene PMID: 11867715 PNAS 2020: By RT-PCR, fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. PMID: 2621361711kb F1000Res: A deletion of the promoter region of APC identified by whole genome sequencing in a patient diagnosed with Familial Adenomatous Polyposis PMID: 33193653 Frontiers in Genetics: Pathogenic or likely pathogenic germline genetic variants in 10.1% of the participants in genes such as APC is described PMID: 33769591: J Clin Lab Anal 2021: Authors report on 59 FAP Iranian patients in 10 families with disease causing variants in APC. The variants were found in exons 10, 14, and 15 of the gene as performed by PCR and the direct sequencing of the entire coding exons. The variants encompass missense, nonsense, and frameshift variants also see PMID: 34259353: WES study implicating APC with pathogenic variants among FAP-like patients pLI = 1; HI = 2.19 , in silico scores suggest haploinsufficiency

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Triplosensitivity is not a known mechanism as focal duplications of APC are rarely reported