Submissions for variant NM_000038.6(APC):c.847C>T (p.Arg283Ter)

dbSNP: rs786201856

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002517615	SCV003836574	pathogenic	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.847C>T (p.Arg283*) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 9 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 15 probands meeting 8 phenotype points. In addition, this variant is also reported in 50 probands with FAP not otherwise specified, meeting more than 16 phenotype points in total (PS4_VeryStrong; PMIDs 30897307, 20924072, 20685668, 10768871, 9950360, 12901799, 11857735, 26625971, 23159591, Bonn internal data). The variant has been reported to segregate with FAP in 5 meioses from 1 family and in 31 members from 1 large FAP family (PP1_Strong; PMID: 12901799, Bonn internal data). The variant is not reported in gnomAD (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4_VeryStrong, PM2_Supporting and PP1_Strong (VCEP specifications version 1; date of approval: 12/12/2022).
Ambry Genetics	RCV000164351	SCV000214984	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-22	criteria provided, single submitter	clinical testing	The p.R283* pathogenic mutation (also known as c.847C>T), located in coding exon 8 of the APC gene, results from a C to T substitution at nucleotide position 847. This changes the amino acid from an arginine to a stop codon within coding exon 8. This pathogenic variant has been detected in multiple families with familial adenomatous polyposis (FAP) across several ethnicities (Enomoto M et al. Jpn. J. Clin. Oncol. 2000 Feb;30:82-8; Mohamed Z et al. Cancer Sci. 2003 Aug;94:725-8; Friedl W et al. Hered. Cancer Clin. Pract, 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; de Oliveira JC et al. Cancer Med, 2019 05;8:2114-2122). 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.
Invitae	RCV003337238	SCV000282846	pathogenic	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg283*) 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). 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: 8187091, 9950360, 12901799, 20223039, 20685668). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 184999). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202113	SCV000567470	pathogenic	not provided	2015-07-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted APC c.847C>T at the cDNA level and p.Arg283Ter (R283X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with a clinical diagnosis of Familial Adenomatous Polyposis and is considered pathogenic (Nagase 1992, Friedl 2005, Torrezan 2013).
Fulgent Genetics, Fulgent Genetics	RCV000763538	SCV000894351	pathogenic	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501350	SCV001363555	pathogenic	Familial multiple polyposis syndrome	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: APC c.847C>T (p.Arg283X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251064 control chromosomes (gnomAD). c.847C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Mohamed_2003, Nagase_1992, Friedl_2005). 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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic, along with one somatic submission also classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202113	SCV002047907	pathogenic	not provided	2021-05-06	criteria provided, single submitter	clinical testing	The APC c.847C>T; p.Arg283Ter variant (rs786201856), is reported in the literature in multiple individuals, and segregates with disease in at least one family affected with familial adenomatous polyposis (Enomoto 2000, Friedl 2005, Miyaki 1994, Mohamed 2003, Nagase 1992, Olschwang 1993, Pang 2001, Rivera 2011, Torrezan 2013, van der Luijt 1997, Wallis 1999). This variant is also reported in ClinVar (Variation ID: 184999). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg283Ter variant is considered to be pathogenic. References: Enomoto M et al. The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis. Jpn J Clin Oncol. 2000 Feb;30(2):82-8. Friedl W et al. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Mohamed Z et al. A nonsense mutation in exon 8 of the APC gene (Arg283Ter) causes clinically variable FAP in a Malaysian Chinese family. Cancer Sci. 2003 Aug;94(8):725-8. Nagase H et al. Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat. 1992;1(6):467-73. Olschwang S et al. Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell. 1993 Dec 3;75(5):959-68. Pang CP et al. Congenital hypertrophy of the retinal pigment epithelium and APC mutations in Chinese with familial adenomatous polyposis. Ophthalmologica. 2001 Nov-Dec;215(6):408-11. Rivera B et al. Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study. Ann Oncol. 2011 Apr;22(4):903-9. Torrezan GT et al. Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations in Brazilian FAP, AFAP, and MAP patients. Orphanet J Rare Dis. 2013 Apr 5;8:54. van der Luijt RB et al. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16. Wallis YL et al. Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition. J Med Genet. 1999 Jan;36(1):14-20.
Myriad Genetics, Inc.	RCV003337238	SCV004044026	pathogenic	Familial adenomatous polyposis 1	2023-04-27	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.
Baylor Genetics	RCV002517615	SCV004209687	pathogenic	Familial adenomatous polyposis 1	2023-08-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202113	SCV000257036	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353622	SCV000591057	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Arg283X variant was identified in 13 of 9480 proband chromosomes (frequency: 0.001) from individuals or families with FAP (Kerr 2013, Friedl 2005, Aretz 2007, Hes 2007, Rivera 2011). The variant was also identified in ClinVar (as pathogenic by Ambry Genetics, Invitae and Mayo Clinic), Cosmic (32 x in large intestine, 1 x in biliary tract, adenocarcinoma), UMD-LSDB (35x), Insight Colon Cancer Gene Variant Database (pathogenicity was reported 49x), Zhejiang Colon Cancer Database (3 x as pathogenic). The variant was not identified in Genesight-COGR and MutDB databases. The variant was not identified the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg283X variant leads to a premature stop codon at position 283, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in FAP 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.
Genome Sciences Centre, British Columbia Cancer Agency	RCV001789763	SCV000693730	pathogenic	Colorectal cancer	2016-07-11	no assertion criteria provided	research