Submissions for variant NM_000038.6(APC):c.3443_3444del (p.Tyr1147_Ser1148insTer)

dbSNP: rs1765424969

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564567	SCV001234190	pathogenic	Familial adenomatous polyposis 1	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1148*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1696 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 (PMID: 18794146). ClinVar contains an entry for this variant (Variation ID: 862344). 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.
Ambry Genetics	RCV003283955	SCV004005218	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The c.3443_3444delCT variant, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3443 to 3444, causing a translational frameshift with a predicted alternate stop codon (p.S1148*). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004564567	SCV004044684	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.