Submissions for variant NM_000038.6(APC):c.5820dup (p.Pro1941fs)

dbSNP: rs1561602876

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002544732	SCV000813454	pathogenic	Familial adenomatous polyposis 1	2021-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro1941Thrfs*8) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 903 amino acid(s) of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 566205). 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.
Myriad Genetics, Inc.	RCV002544732	SCV004044863	pathogenic	Familial adenomatous polyposis 1	2023-05-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Ambry Genetics	RCV004639318	SCV005143442	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-30	criteria provided, single submitter	clinical testing	The c.5820dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 5820, causing a translational frameshift with a predicted alternate stop codon (p.P1941Tfs*8). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 32% 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 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.