5-112839978-AAGAG-AAG
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.4393_4394del (p.Ser1465TrpfsTer3) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 4 probands meeting 4 phenotype points (PS4_Strong, [PMID:1316610, 28018803, 29998021, 28782241, 10768871]). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4_Strong and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA009520/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 frameshift
Scores
Clinical Significance
Conservation
Publications
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- APC-related attenuated familial adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Turcot syndrome with polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 13 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | MANE Select | c.4393_4394delAG | p.Ser1465TrpfsTer3 | frameshift | Exon 16 of 16 | NP_000029.2 | ||
| APC | NM_001407446.1 | c.4477_4478delAG | p.Ser1493TrpfsTer3 | frameshift | Exon 16 of 16 | NP_001394375.1 | |||
| APC | NM_001354896.2 | c.4447_4448delAG | p.Ser1483TrpfsTer3 | frameshift | Exon 17 of 17 | NP_001341825.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | TSL:5 MANE Select | c.4393_4394delAG | p.Ser1465TrpfsTer3 | frameshift | Exon 16 of 16 | ENSP00000257430.4 | ||
| APC | ENST00000508376.6 | TSL:1 | c.4393_4394delAG | p.Ser1465TrpfsTer3 | frameshift | Exon 17 of 17 | ENSP00000427089.2 | ||
| APC | ENST00000508624.5 | TSL:1 | n.*3715_*3716delAG | non_coding_transcript_exon | Exon 17 of 17 | ENSP00000424265.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727244 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:4Uncertain:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
The NM_000038.6(APC):c.4393_4394del (p.Ser1465TrpfsTer3) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 4 probands meeting 4 phenotype points (PS4_Strong, [PMID: 1316610, 28018803, 29998021, 28782241, 10768871]). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4_Strong and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023).
This sequence change creates a premature translational stop signal (p.Ser1465Trpfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1379 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with APC-related disease, including familial adenomatous polyposis and Gardner syndrome (PMID: 1316610, 10768871, 20685668, 26840078, 28018803, 28782241). This variant is also known as a 2-bp deletion (AG) at codon 1465, 4292-4293delGA and AG del. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, internal data). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP4;PM2;PVS1
not provided Pathogenic:4
The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
PVS1, PM2, PP4, PP5
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8281160, 11553046, 8162051, 28222664, 20924072, 12010888, 29367705, 15040027, 17653897, 8187091, 12378616, 24416237, 26840078, 8990002, 19509103, 24005794, 23159591, 27087319, 20434453, 15108288, 28018803, 9824584, 26681312, 29998021, 28782241, 33082750, 34199654, 32198650, 31547110, 31754633, 1316610, 10768871, 16134147, 8730280, 20223039)
Familial multiple polyposis syndrome Pathogenic:1
Variant summary: APC c.4393_4394delAG (p.Ser1465TrpfsX3) results in a premature termination codon and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant was absent in 251224 control chromosomes (gnomAD). c.4393_4394delAG has been reported in the literature in individuals affected with familial adenomatous polyposis, colorectal cancer and Gardner fibroma and has been found to segregate with disease in at least one family (e.g. deOliverira_2022, Miyoshi_1992, Schafer_2016, Neffa_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35534704, 1316610, 28018803, 29998021). ClinVar contains an entry for this variant (Variation ID: 811). Based on the evidence outlined above, the variant was classified as pathogenic.
Periampullary adenoma Pathogenic:1
Carcinoma of colon Pathogenic:1
The p.Ser1465TrpfsX3 variant has been reported in the literature in 11/1576 probands with FAP or AFAP and extracolonic features (Enomoto_2000_10768871, Friedl_2005_20223039). The p.Ser1465TrpfsX3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1465 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the APC gene. In summary, based on the above information, this variant meets our criteria for pathogenicity.
Colorectal cancer, susceptibility to Pathogenic:1
Gardner syndrome Pathogenic:1
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.4393_4394delAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 4393 to 4394, causing a translational frameshift with a predicted alternate stop codon (p.S1465Wfs*3). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 48% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported in numerous individuals and families diagnosed with FAP, including families presenting with the Gardner syndrome phenotype (Miyoshi Y et al. Proc Natl Acad Sci USA, 1992 May 15;89(10):4452-6; Dobbie Z et al. J Med Genet, 1996 Apr;33(4):274-80; Friedl W and Aretz S. Hered Cancer Clin Pract, 2005 Sep 15;3(3):95-114; Rivera B et al. Ann Oncol, 2011 Apr;22(4):903-9; Torrezan GT et al. Orphanet J Rare Dis, 2013 Apr;8:54; Schäfer M et al. European J Pediatr Surg Rep, 2016 Dec;4:17-21; Yu F et al. J. Cell. Mol. Med, 2018 Jan;22:152-162; Neffa F et al. J Gastrointest Oncol, 2018 Jun;9:553-559). An individual with unexplained polyposis was also found to be mosaic for this mutation (Ciavarella M et al. Eur J Hum Genet, 2018 03;26:387-395). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at