Submissions for variant NM_000038.6(APC):c.2805del (p.Thr934_Tyr935insTer)

dbSNP: rs398123120

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174983	SCV000226398	pathogenic	not provided	2012-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433583	SCV002745797	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-24	criteria provided, single submitter	clinical testing	The c.2805delC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 2805, causing a predicted alternate stop codon (p.Y935*). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1909 amino acids of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). In addition, this variant was identified in 1/51 unrelated Argentinean probands affected by familial adenomatous polyposis (FAP) (De Rosa M et al. Hum. Mutat., 2004 May;23:523-4). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514367	SCV003525742	pathogenic	Familial adenomatous polyposis 1	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr935*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1909 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 (FAP) (PMID: 10083733, 10713886, 15108288). ClinVar contains an entry for this variant (Variation ID: 92344). 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.	RCV002514367	SCV004044884	pathogenic	Familial adenomatous polyposis 1	2023-05-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.