Submissions for variant NM_000038.6(APC):c.2413C>T (p.Arg805Ter)

dbSNP: rs587779783

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562255	SCV000219025	pathogenic	Familial adenomatous polyposis 1	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg805*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2039 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 8730280, 19531215, 20223039, 20649969, 20924072, 30897307). ClinVar contains an entry for this variant (Variation ID: 127281). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115073	SCV000273569	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	The p.R805* pathogenic mutation (also known as c.2413C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2413. This changes the amino acid from an arginine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 257 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was previously described in an individual with polyposis and a family history of colorectal cancer (Dobbie Z et al. J. Med. Genet. 1996 Apr; 33(4):274-80). It was also seen in two individuals diagnosed with familial adenomatous polyposis (FAP) (Gutierrez Sanchez LH et al. Gastrointest. Endosc. 2018 Mar;87(3):648-656.e3). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501097	SCV000591111	pathogenic	Familial multiple polyposis syndrome	2015-09-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001270020	SCV001450443	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001292808	SCV001481466	pathogenic	Desmoid disease, hereditary	2020-10-15	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8730280, 30897307; ClinVar 127281]
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501097	SCV002014915	pathogenic	Familial multiple polyposis syndrome	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: APC c.2413C>T (p.Arg805X) results in a premature termination codon located in the last exon, which is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein, removing the basic domain (amino acids 2224-2575; IPR009234) and the EB-1 binding domain (amino acid 2670-2843; IPR009232). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250860 control chromosomes (gnomAD). c.2413C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Dobbie_1996, Iaquinto_2008, deOliveira_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV004562255	SCV004044755	pathogenic	Familial adenomatous polyposis 1	2023-05-04	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.
PreventionGenetics, part of Exact Sciences	RCV003935094	SCV004752514	pathogenic	APC-related disorder	2024-01-03	criteria provided, single submitter	clinical testing	The APC c.2413C>T variant is predicted to result in premature protein termination (p.Arg805*). This variant has been reported in individuals with adenomatous polyposis coli (Table 1, Dobbie et al. 1996. PubMed ID: 8730280; Tables 1 and 4, de Oliveira et al. 2019. PubMed ID: 30897307; Table 1, Lee et al. 2022. PubMed ID: 35189564). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127281/). Nonsense variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997211	SCV004822627	pathogenic	Classic or attenuated familial adenomatous polyposis	2023-07-09	criteria provided, single submitter	clinical testing	The c.2413C>T (p.Arg805*) variant in the APC gene is located on the exon 16 and is predicted to introduce a premature translation termination codon (p.Arg805*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 30897307, 31113927, 26446593, 19029688, 20649969). Loss-of-function variants of APC are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with familial adenomatous polyposis/colorectal cancer (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 127281). The variant is absent in the general population database (gnomAD). Therefore, the c.2413C>T (p.Arg805*) variant of APC has been classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001270020	SCV005199555	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001270020	SCV001742857	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001270020	SCV001953278	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824606	SCV002074963	not provided	Familial adenomatous polyposis 1; Gastric adenocarcinoma and proximal polyposis of the stomach; APC-related attenuated familial adenomatous polyposis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.