Submissions for variant NM_000038.6(APC):c.4391_4394del (p.Glu1464fs)

dbSNP: rs387906234

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562182	SCV000552497	pathogenic	Familial adenomatous polyposis 1	2023-04-20	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 812). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 15108286, 16088911, 20223039, 20685668, 21643010, 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1464Valfs*8) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1380 amino acid(s) of the APC protein. For these reasons, this variant has been classified as Pathogenic. 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.
Ambry Genetics	RCV000565829	SCV000676354	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	The c.4391_4394delAGAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 4391 to 4394, causing a translational frameshift with a predicted alternate stop codon (p.E1464Vfs*8). This mutation has been reported in multiple patients with a clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP) (Armstrong JG et al. Hum. Mutat., 1997;10:376-80; Gismondi V et al. Hum. Mutat., 1997;9:370-3; Bisgaard ML et al. Hum. Mutat., 2004 May;23:522; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Kim DW et al. Hum. Mutat., 2005 Sep;26:281; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Rohlin A et al. Oncogene, 2011 Dec;30:4977-89; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). 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.
GeneKor MSA	RCV000565829	SCV000821695	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes four bases from exon 11 of the APC mRNA (c.4391_4394delAGAG), causing a frameshift after codon 1464 and the creation of a premature translation stop signal 8 amino acid residues later, p.(Glu1464Valfs). This is expected to result in an absent or disrupted protein product. This sequence change has been reported in the literature in individuals affected with familial adenomatous polyposis (FAP) (PMID: 20685668, 15108286, 16088911, 21643010, 20223039, 23159591). Truncating variants in APC are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID:812).
Color Diagnostics, LLC DBA Color Health	RCV000565829	SCV001735615	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individuals affected with familial adenomatous polyposis (FAP; PMID: 15108286, 16088911, 20223039, 21643010), an FAP somatic mosaicism case (PMID: 17486639), and a Gardner fibroma case in the literature (PMID: 29026543). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV004562182	SCV004044735	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.
GeneDx	RCV004719602	SCV005325260	pathogenic	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4393del4; This variant is associated with the following publications: (PMID: 9101302, 16088911, 21643010, 17486639, 20685668, 20223039, 29026543, 23159591, 15108286, 31159747, 34873480)
OMIM	RCV000000851	SCV000021001	pathogenic	Periampullary adenoma	1993-11-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500484	SCV000591171	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Glu1464ValfsX8 deletion has been previously reported in the literature in 1 of 54 chromosomes from individuals with familial adenomatous polyposis (Gismondi 1997). is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1464 and leads to a premature stop codon 8 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of FAP. Notably, this deletion occurs in the last exon of the APC gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate the hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. However, this is the type of alteration that is expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.