Submissions for variant NM_000038.6(APC):c.2804dup (p.Tyr935Ter) (rs863225332)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410020	SCV000488316	likely pathogenic	Familial adenomatous polyposis 1	2016-02-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000202260	SCV000568275	pathogenic	not provided	2018-05-29	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted APC c.2804dupA at the cDNA level and p.Tyr935Ter (Y935X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTT[dupA]CAAT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon, and is predicted to cause loss of normal protein function through protein truncation. Even though this nonsense variant occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 1909 amino acids are no longer translated. APC c.2804dupA, previously reported as APC 2803insA, has been shown to result in a truncated protein by a protein truncation assay (Scarano 1999) and has been reported in association with familial adenomatous polyposis (FAP) (Scarano 1999, De Rosa 2003, Lagarde 2010, Kerr 2013, Kohda 2016, Pearlman 2016). This variant is considered pathogenic.
Ambry Genetics	RCV000490899	SCV000579798	pathogenic	Hereditary cancer-predisposing syndrome	2017-06-08	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae	RCV000410020	SCV000829754	pathogenic	Familial adenomatous polyposis 1	2019-01-03	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the APC gene (p.Tyr935). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1909 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with familial adenomatous polyposis (PMID: 10090483, 20685668, 28533537, 23159591). This variant is also known as c.2803insA in the literature. ClinVar contains an entry for this variant (Variation ID: 217954). A different truncation (p.Gln1062) that lies downstream of this variant has been determined to be pathogenic (PMID: 1316610, 8162022, 15771908). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000202260	SCV000256954	pathogenic	not provided		no assertion criteria provided	research

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