ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4393_4394del (p.Ser1465fs) (rs387906234)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV000202100 SCV000256996 pathogenic not provided 2019-12-16 criteria provided, single submitter clinical testing PVS1, PM2, PP4, PP5
University of Washington Department of Laboratory Medicine, University of Washington RCV000210178 SCV000266008 pathogenic Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000202100 SCV000279573 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in APC is denoted c.4393_4394delAG at the cDNA level and p.Ser1465TrpfsX3 (S1465WfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAG[delAG]TGGA. The deletion causes a frameshift which changes a Serine to a Tryptophan at codon 1465, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC c.4393_4394delAG has been observed in many families with Familial Adenomatous Polyposis (Miyoshi 1992, Dobbie 1996, Enomoto 2000, Aceto 2005, Friedl 2005, Castellsagu? 2010, Schafer 2016, Neffa 2018). We consider this variant to be pathogenic.
Invitae RCV000646370 SCV000768139 pathogenic Familial adenomatous polyposis 1 2018-10-13 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Ser1465Trpfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1379 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with APC-related disease, including familial adenomatous polyposis and Gardner syndrome (PMID: 1316610, 10768871, 20685668, 28782241, 28018803, 26840078). This variant is also known as a 2-bp deletion (AG) at codon 1465, 4292-4293delGA and AG del in the literature. ClinVar contains an entry for this variant (Variation ID: 811). A different truncation (p.Asn1979Thrfs*64) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 20434453, 26681312). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202100 SCV001133336 pathogenic not provided 2019-02-26 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV001022414 SCV001184146 pathogenic Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing 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 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 U S A. 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;8:5; 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 Gastrointestinal Oncology. 2017. Epub Ahead of Print). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000202100 SCV001762013 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
OMIM RCV000000849 SCV000020999 pathogenic Gardner syndrome 2001-08-01 no assertion criteria provided literature only
OMIM RCV000000850 SCV000021000 pathogenic Periampullary adenoma 2001-08-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502554 SCV000591172 pathogenic Carcinoma of colon no assertion criteria provided clinical testing 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.