Submissions for variant NM_000038.6(APC):c.1657del (p.Trp553fs)

dbSNP: rs1114167594

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490917	SCV000579898	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The c.1657delT pathogenic mutation, located in coding exon 13 of the APC gene, results from a deletion of one nucleotide at nucleotide position 1657, causing a translational frameshift with a predicted alternate stop codon (p.W553Gfs*5). This pathogenic mutation has been reported in the literature in a French familial adenomatous polyposis (FAP) cohort and in an 11-year-old medulloblastoma patient who had a family history of FAP (Augustyn AM and Wallerstein R. Clin Pediatr (Phila). 2009 Jul;48(6):623-6; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004564219	SCV000768064	pathogenic	Familial adenomatous polyposis 1	2024-08-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp553Glyfs*5) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 428155). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004564219	SCV004044876	pathogenic	Familial adenomatous polyposis 1	2023-05-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503404	SCV000591084	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Trp553GlyfsX5 variant was not identified in the literature nor was it identified in dbSNP, Clinvitae database, COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database. It was identified in UMD (2x as causal). The variant was not identified in control databases; NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC). The c.1657delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 553 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.