Submissions for variant NM_000038.6(APC):c.5804dup (p.Ser1936fs)

dbSNP: rs863225367

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563122	SCV000552784	pathogenic	Familial adenomatous polyposis 1	2024-09-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1936Valfs*13) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 908 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 217997). 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, internal data). 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.
GeneDx	RCV000202250	SCV000779062	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in APC is denoted c.5804dupA at the cDNA level and p.Ser1936ValfsX13 (S1936VfsX13) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCCCC[dupA]GTCA. The duplication causes a frameshift which changes a Serine to a Valine at codon 1936, and creates a premature stop codon at position 13 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. We consider this variant to be pathogenic.
Ambry Genetics	RCV002354570	SCV002649010	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	The c.5804dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 5804, causing a translational frameshift with a predicted alternate stop codon (p.S1936Vfs*13). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 31% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This pathogenic variant has been detected in multiple families with a clinical diagnosis of familial adenomatous polyposis (FAP) (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 alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004563122	SCV004044004	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202250	SCV000257017	likely pathogenic	not provided		no assertion criteria provided	research