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

dbSNP: rs387906234

Total submissions: 14

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	2022-03-08	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003989278	SCV000768139	pathogenic	Familial adenomatous polyposis 1	2023-12-18	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 811). 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, Invitae). 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	2021-11-03	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 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). 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
Myriad Genetics, Inc.	RCV003989278	SCV004044688	pathogenic	Familial adenomatous polyposis 1	2023-05-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689397	SCV005184957	pathogenic	Familial multiple polyposis syndrome	2024-05-09	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV003989278	SCV005199949	pathogenic	Familial adenomatous polyposis 1	2024-08-26	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP4;PM2;PVS1
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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989278	SCV004807664	uncertain significance	Familial adenomatous polyposis 1	2024-03-29	flagged submission	clinical testing