Submissions for variant NM_000038.6(APC):c.3807_3808del (p.Ile1269fs)

dbSNP: rs786203760

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167206	SCV000218043	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	The c.3807_3808delAT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3807 to 3808, causing a translational frameshift with a predicted alternate stop codon (p.I1269Mfs*6). This variant has been observed in individuals with a personal and/or family history that is consistent with Familial Adenomatous Polyposis syndrome (FAP) (Plawski A et al. J Appl Genet, 2008;49:407-14; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202002	SCV000617339	pathogenic	not provided	2017-04-14	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in APC is denoted c.3807_3808delAT at the cDNA level and p.Ile1269MetfsX6 (I1269MfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAT[delAT]GTTT. The deletion causes a frameshift which changes an Isoleucine to a Methionine at codon 1269, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC Ile1269MetfsX6 has been observed in at least one individual with Familial Adenomatous Polyposis (Plawski 2008). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562381	SCV000647477	pathogenic	Familial adenomatous polyposis 1	2022-02-01	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.Ile1269Metfs*6) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1575 amino acid(s) of the APC protein. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 19029688). ClinVar contains an entry for this variant (Variation ID: 187473). 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.	RCV004562381	SCV004044726	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202002	SCV000256978	pathogenic	not provided		no assertion criteria provided	research