Submissions for variant NM_000038.6(APC):c.8513dup (p.Tyr2838Ter)

dbSNP: rs869312786

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210080	SCV000266146	uncertain significance	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563141	SCV001389461	uncertain significance	Familial adenomatous polyposis 1	2022-02-04	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 224555). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr2838*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the APC protein.
Ambry Genetics	RCV002286721	SCV002577353	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The c.8513dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 8513, causing a translational frameshift with a predicted alternate stop codon (p.Y2838*). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). In addition, this mutation, as well as two other alterations resulting in the same premature truncation (c.8514C>A and c.8514C>G) have been identified in individuals with familial adenomatous polyposis (Ambry internal data; personal communication). 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.