Submissions for variant NM_000038.6(APC):c.3440dup (p.Tyr1147Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002457119	SCV002617121	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The c.3440dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 3440, causing a translational frameshift with a predicted alternate stop codon (p.Y1147*). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1697 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003337395	SCV004045720	pathogenic	Familial adenomatous polyposis 1	2023-05-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003337395	SCV004292811	pathogenic	Familial adenomatous polyposis 1	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1147*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1697 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 personal and/or family history of APC-related conditions (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 1731467). 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.