Submissions for variant NM_000038.6(APC):c.3814del (p.Ser1272fs)

dbSNP: rs587783033

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002354330	SCV002623364	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The c.3814delT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 3814, causing a translational frameshift with a predicted alternate stop codon (p.S1272Qfs*16). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 55% 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). In a large (n=1591) series of patients referred for APC testing, this alteration was detected in one individual (Kerr SE et al. J Mol Diagn. 2013 Jan;15:31-43). 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.	RCV000144569	SCV004044923	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144569	SCV004292814	pathogenic	Familial adenomatous polyposis 1	2023-09-05	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 156479). This premature translational stop signal has been observed in individual(s) with a personal or family history of APC-related conditions (PMID: 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1272Glnfs*16) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1572 amino acid(s) of the APC protein. 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.
All of Us Research Program, National Institutes of Health	RCV003998158	SCV004834538	likely pathogenic	Classic or attenuated familial adenomatous polyposis	2024-01-18	criteria provided, single submitter	clinical testing	This variant creates a premature termination codon in the last exon. The transcribed mRNA is predicted to escape nonsense mediated decay and result in protein truncation. This prediction has not been confirmed by functional studies. To date, this variant has been identified in one individual referred for APC testing (PMID: 23159591). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Pathway Genomics	RCV000144569	SCV000189862	pathogenic	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing