Submissions for variant NM_000038.6(APC):c.3196del (p.Arg1066fs)

dbSNP: rs878853436

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516269	SCV000282732	pathogenic	Familial adenomatous polyposis 1	2021-10-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1066Aspfs*60) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1778 amino acid(s) of the APC protein. This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 20685668). ClinVar contains an entry for this variant (Variation ID: 236586). For these reasons, this variant has been classified as Pathogenic. 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284351	SCV001470096	pathogenic	not provided	2019-11-26	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Myriad Genetics, Inc.	RCV002516269	SCV004045658	pathogenic	Familial adenomatous polyposis 1	2023-05-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001284351	SCV004562532	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	The APC c.3196del; p.Arg1066AspfsTer60 variant (rs878853436) is reported in the literature in at least one individual affected with familial adenomatous polyposis (FAP; Lagarde 2010). This variant is also reported in ClinVar (Variation ID: 236586), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with FAP and are considered pathogenic (Lagarde 2010). Based on available information, this variant is considered to be pathogenic. References: Lagarde A et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. 2010 Oct;47(10):721-2. PMID: 20685668.