Submissions for variant NM_000038.6(APC):c.3146G>A (p.Trp1049Ter)

dbSNP: rs876658667

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216288	SCV000274214	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.W1049* pathogenic mutation (also known as c.3146G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3146. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant was previously described in individuals with familial adenomatous polyposis (Friedl W, et al. Hered Cancer Clin Pract 2005 ; 3(3):95-114; Moisio AL, et al. Gut 2002 Jun; 50(6):845-50). In addition to the clinical data presented in the literature, 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508021	SCV000602538	pathogenic	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003335247	SCV000647430	pathogenic	Familial adenomatous polyposis 1	2023-08-30	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 230610). For these reasons, this variant has been classified as Pathogenic. 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. 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. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 12010888, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1049*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1795 amino acid(s) of the APC protein.
Myriad Genetics, Inc.	RCV003335247	SCV004044784	pathogenic	Familial adenomatous polyposis 1	2023-05-05	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.