Submissions for variant NM_000038.6(APC):c.3471_3474del (p.Glu1157fs)

dbSNP: rs786203020

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166142	SCV000216914	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-08	criteria provided, single submitter	clinical testing	The c.3471_3474delGAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 3471 to 3474, causing a translational frameshift with a predicted alternate stop codon (p.E1157Dfs*7). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 40.9% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been reported in multiple individuals with a clinical diagnosis of familial adenomatous polyposis or attenuated familial adenomatous polyposis (Norheim Andersen S et al. Scand. J. Gastroenterol.1999 Jun;34:611-7; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Soravia C et al. Int J Colorectal Dis. 2006 Jan;21:79-83; Andresen PA et al. J. Cancer Res. Clin. Oncol. 2009 Oct;135:1463-70; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226886	SCV000282743	pathogenic	Familial adenomatous polyposis 1	2016-03-02	criteria provided, single submitter	clinical testing	This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.3471_3474delGAGA), causing a frameshift at codon 1157. This creates a premature translational stop signal (p.Glu1157Aspfs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in patients affected with familial adenomatous polyposis (PMID: 10440612, 16676398, 20685668, 17411426, 20223039). For these reasons, this variant has been classified as Pathogenic.
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000226886	SCV002104260	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226886	SCV002195665	pathogenic	Familial adenomatous polyposis 1	2023-08-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1157Aspfs*7) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1687 amino acid(s) of the APC protein. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10440612, 16676398, 17411426, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 186532). 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.
Myriad Genetics, Inc.	RCV000226886	SCV004044666	pathogenic	Familial adenomatous polyposis 1	2023-05-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.