Submissions for variant NM_000038.6(APC):c.1875_1878del (p.Asn627fs)

dbSNP: rs878853420

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650516	SCV000282705	pathogenic	Familial adenomatous polyposis 1	2023-04-07	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 8381580, 19029688, 20685668, 20924072). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn627Leufs*2) 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). ClinVar contains an entry for this variant (Variation ID: 236565). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001013490	SCV001174083	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The c.1875_1878delGACA pathogenic mutation, located in coding exon 14 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 1875 to 1878, causing a translational frameshift with a predicted alternate stop codon (p.N627Lfs*2). This mutation (designated CAGACA->CA) was first reported in 1/160 French patients with adenomatous polyposis (Olschwang S et al. Am. J. Hum. Genet., 1993 Feb;52:273-9), and it has since been identified in 3/934 French patients with familial adenomatous polyposis (FAP) (Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2), 1/300 unrelated Polish FAP families (Plawski A et al. J. Appl. Genet., 2008;49:407-14), and 1/136 Spanish families with classical FAP (Rivera B et al. Ann. Oncol., 2011 Apr;22:903-9). 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.
Myriad Genetics, Inc.	RCV002516261	SCV004044634	pathogenic	Familial adenomatous polyposis 1	2023-05-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000582565	SCV000691721	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355311	SCV001550166	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Asn627LeufsX2 variant was identified in 3 of 1192 proband chromosomes (frequency: 0.003) from French, Spanish and Polish individuals or families with FAP (Olschwang 1993, Plawski 2008, Rivera 2011). The variant was identified in the following databases: Clinvitae (as pathogenic), COSMIC (1x in an adenocarcinoma), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar (pathogenic by Invitae), and UMD (1x with a “causal” classification); but the variant was not identified in dbSNP, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), COGR, MutDB, or the Zhejiang Colon Cancer Database (LOVD). The c.1875_1878del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 627 and leads to a premature stop codon 2 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.