Submissions for variant NM_000038.6(APC):c.1239dup (p.Arg414fs)

dbSNP: rs879254088

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235625	SCV000293416	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23159591, 19444466)
Invitae	RCV002518443	SCV000552616	pathogenic	Familial adenomatous polyposis 1	2022-01-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 246085). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 19444466, 23159591). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg414Thrfs*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).
Ambry Genetics	RCV001010499	SCV001170707	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-05	criteria provided, single submitter	clinical testing	The c.1239dupA pathogenic mutation, located in coding exon 9 of the APC gene, results from a duplication of A at nucleotide position 1239, causing a translational frameshift with a predicted alternate stop codon (p.R414Tfs*5). This mutation has been previously reported in families with classic FAP presentation, as well as extracolonic tumors, such as hepatocellular, pancreatic and duodenal cancers (Kerr SE et al. J Mol Diagn 2013 Jan; 15(1):31-43; Andresen PA et al. J. Cancer Res. Clin. Oncol. 2009 Oct; 135(10):1463-70). 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.	RCV002518443	SCV004044694	pathogenic	Familial adenomatous polyposis 1	2023-04-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV001010499	SCV004361866	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 19444466, 23159591). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.