Submissions for variant NM_000038.6(APC):c.3810T>A (p.Cys1270Ter)

dbSNP: rs863225347

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000202149	SCV000292998	pathogenic	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3810T>A at the cDNA level and p.Cys1270Ter (C1270X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through protein truncation. APC Cys1270Ter results in the loss of 1574 amino acids and several protein domains are disrupted by the truncation (Azzopardi 2008, UniProt). This variant has been reported in individuals with adenomatous polyposis (Su 2000, Wu 2004, Kerr 2013) and is considered pathogenic.
Ambry Genetics	RCV000490989	SCV000579844	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-02	criteria provided, single submitter	clinical testing	The p.C1270* pathogenic mutation (also known as c.3810T>A) located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 3810. This changes the amino acid from a cysteine to a stop codon within coding exon 15. This mutation has been previously identified in one kindred with FAP/AFAP (Su LK et al. Hum. Genet. 2000 Jan; 106(1):101-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202149	SCV000600090	pathogenic	not provided	2020-05-31	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562426	SCV000953481	pathogenic	Familial adenomatous polyposis 1	2023-08-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 217972). For these reasons, this variant has been classified as Pathogenic. 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. 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. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10982189, 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys1270*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1574 amino acid(s) of the APC protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298521	SCV002598585	pathogenic	Familial multiple polyposis syndrome	2022-09-01	criteria provided, single submitter	clinical testing	Variant summary: APC c.3810T>A (p.Cys1270X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Truncations downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant was absent in 250546 control chromosomes (gnomAD). c.3810T>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (examples: Su_2000, Wu_2001, Kerr_2013, and Findlen_2021). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV004562426	SCV004043968	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004562426	SCV005688744	pathogenic	Familial adenomatous polyposis 1	2023-08-19	criteria provided, single submitter	clinical testing	The APC c.3810T>A (p.Cys1270Ter) variant has been reported in several individuals affected with familial adenomatous polyposis (Kerr SE et al., PMID: 23159591; Su LK et al., PMID: 10982189; Wu G et al., PMID: 11960572). This variant has been reported in the ClinVar database as a germline pathogenic variant by six submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay, but is predicted to delete more than 1500 amino acids. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202149	SCV000256979	pathogenic	not provided		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003982949	SCV004800287	pathogenic	APC-related disorder	2024-02-05	no assertion criteria provided	clinical testing	The APC c.3810T>A variant is predicted to result in premature protein termination (p.Cys1270*). This nonsense variant is located in the last exon of the APC gene and is expected to disrupt the last 1574 amino acid(s) of the APC protein. This variant has been reported in individuals with Familial Adenomatous Polyposis (examples: Kerr SE et al 2012. PubMed ID: 23159591). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/217972/). This variant is interpreted as pathogenic.