Submissions for variant NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)

dbSNP: rs387906236

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512626	SCV000768087	pathogenic	Familial adenomatous polyposis 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1538Ilefs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1306 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 familial adenomatous polyposis (PMID: 8162051, 8594558, 20223039, 20513532, 20685668, 21643010, 21779980, 22987206). ClinVar contains an entry for this variant (Variation ID: 823). 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.
Genetic Services Laboratory, University of Chicago	RCV001781152	SCV002067521	pathogenic	not provided	2020-07-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336071	SCV002639069	pathogenic	Hereditary cancer-predisposing syndrome	2015-07-28	criteria provided, single submitter	clinical testing	The c.4612_4613delGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 4612 and 4613, causing a translational frameshift with a predicted alternate stop codon. This mutation has been detected in multiple individuals with clinical diagnoses of AFAP or FAP (Friedl W, et al. Hered Cancer Clin Pract 2005;3(3):95-114, Vandrovcová J, et a. Hum. Mutat. 2004;23(4):397, Jang YH, et al. Cancer Genet. Cytogenet. 2010;200(1):34-9, Gayther SA, et al. Hum. Mol. Genet. 1994;3(1):53-6, Armstrong JG, et al. Hum. Mutat. 1997;10(5):376-80). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227591	SCV003924235	pathogenic	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2021-03-30	criteria provided, single submitter	clinical testing	APC NM_000038.5 exon 15 p.Glu1538Ilefsx5 (c.4612_4613del): This variant has been reported in the literature in at least 8 individuals with Familial Adenomatous Polyposis (FAP) (Gayther 1994 PMID:8162051, Friedl 2005 PMID:20223039, Jang 2010 PMID:20513532, Lagarde 2010 PMID:20685668, Jarry 2011 PMID:21779980, Rohlin 2011 PMID:21643010, Schwarzova 2013 PMID:22987206). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:823). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of two nucleotides and creates a premature stop codon 5 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Zhang 2017 PMID:28423402). Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However this variant is predicted to affect approximately 45% of the protein and other variants downstream have been reported as Pathogenic. Furthermore, evidence in the literature suggests that variants cluster in this region (Gayther 1994 PMID:8162051). In summary, this variant is classified as pathogenic based on the data above.
Myriad Genetics, Inc.	RCV002512626	SCV004044003	pathogenic	Familial adenomatous polyposis 1	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV002512626	SCV004200474	pathogenic	Familial adenomatous polyposis 1	2023-11-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017217	SCV004848434	pathogenic	Familial multiple polyposis syndrome	2020-07-28	criteria provided, single submitter	clinical testing	The p.Glu1538IlefsX5 variant in APC has been previously reported in at least 6 individuals with APC-associated polyposis conditions: 3 with familial adenomatous polyposis (FAP), 3 individuals with Gardner syndrome, and 4 individuals with suspected FAP (Gayther 1994 PMID: 8162051, Armstrong 1997 PMID: 9375853, Friedl 2005 PMID: 20223039, Jang 2010 PMID: 20513532, Lagarde 2010 PMID: 20685668, Jarry 2011 PMID: 21779980, Rohlin 2011 PMID: 21643010, Schwarzová 2013 PMID: 22987206). This variant was also reported by other clinical laboratories in ClinVar (Variation ID: 823) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1538 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~46% of the coding region, with 1302 amino acids removed. Truncating variants in the last exon of APC, including multiple variants downstream of this variant, have been reported in individuals with FAP. Furthermore, this truncation is predicted to remove the EB1 and APC-basic domains of the APC protein, and in vitro studies have shown that these domains are important regions for APC-mediated microtubule stability and F-actin interactions (Moseley 2007 PMID 17293347, Wen 2004 PMID 15311282). In summary, this variant meets criteria to be classified as pathogenic for APC-associated polyposis conditions, including autosomal dominant FAP and Gardner syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Strong.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001781152	SCV005196611	pathogenic	not provided	2023-07-05	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002512626	SCV005417834	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4+PP1_Moderate
OMIM	RCV000000866	SCV000021016	pathogenic	Gardner syndrome	1997-01-01	no assertion criteria provided	literature only