Submissions for variant NM_000038.6(APC):c.646C>T (p.Arg216Ter)

gnomAD frequency: 0.00001  dbSNP: rs62619935

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115111	SCV000149020	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Nonsense 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: 8882870, 18433509, 16134147, 19347965, 25525159, 10470088, 14523376, 26446593, 20924072, 20685668, 11960572, 12173026, 11741105, 8187091, 20223039, 17486639, 17604324, 10083733, 17411426, 16088911, 19531215, 19029688, 16317745, 25907321, 31062380, 29122597, 31278746, 31852928)
Ambry Genetics	RCV000223521	SCV000276254	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-21	criteria provided, single submitter	clinical testing	The p.R216* pathogenic mutation (also known as c.646C>T), located in coding exon 6 of the APC gene, results from a C to T substitution at nucleotide position 646. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been identified in numerous FAP patients/families of multiple different ethnicities (Miyaki M et al. Cancer Res. 1994 Jun;54:3011-20; Won YJ et al. J. Hum. Genet., 1999;44:103-8; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Stekrova J et al. BMC Med. Genet., 2007 Apr;8:16; Kanter-Smoler G et al. BMC Med, 2008 Apr;6:10; Plawski A et al. J. Appl. Genet., 2008;49:407-14; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003460798	SCV000552465	pathogenic	Familial adenomatous polyposis 1	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg216*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 10470088, 15108286, 16088911, 17411426, 19531215, 20685668, 23159591, 26446593). ClinVar contains an entry for this variant (Variation ID: 127312). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115111	SCV000888762	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals affected with familial adenomatous polyposis in the published literature (PMID: 19531215 (2009), 17411426 (2007), 16088911 (2005), 10470088 (1999), 8187091 (1994)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763536	SCV000894349	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
Revvity Omics, Revvity	RCV000115111	SCV002017673	pathogenic	not provided	2019-08-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281931	SCV002571080	pathogenic	Familial multiple polyposis syndrome	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: APC c.646C>T (p.Arg216X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250150 control chromosomes (gnomAD). c.646C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Aretz_2004, Rivera_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003460798	SCV004044638	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	RCV003460798	SCV004207194	pathogenic	Familial adenomatous polyposis 1	2023-02-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997226	SCV004837300	pathogenic	Classic or attenuated familial adenomatous polyposis	2023-05-31	criteria provided, single submitter	clinical testing	The c.646C>T (p.Arg216*) variant in the APC gene is located on the exon 7 and introduces a premature translation termination codon (p.Arg216*), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with familial adenomatous polyposis/colorectal cancer (PMID: 32504335, 33279946, 26917275, 26900293, 31062380, 19531215). Loss-of-function variants of APC are known to be pathogenic (PMID: 1338904, 17963004). The variant is reported in ClinVar as pathogenic (ID: 127312). The variant is rare in the general population according to gnomAD (1/250150). Therefore, the c.646C>T (p.Arg216*) variant of APC has been classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003460798	SCV005324803	pathogenic	Familial adenomatous polyposis 1	2024-09-04	criteria provided, single submitter	clinical testing	A heterozygous splice-site proximal nonsense variation in exon 7 of the APC gene that results in a stop codon and premature truncation of the protein at codon 216 was detected. The observed variation has previously been reported in individual(s) with familial adenomatous polyposis (FAP) [PMID: 16088911, 17411426, 19531215, 23159591, 26446593]. It is documented as pathogenic in familial adenomatous polyposis 1 in the ClinVar database [VCV000127312.22]. The p.Arg216Ter variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.0006% and 0.0004% in the gnomAD V3.0 and gnomAD V2.1 database, respectively. The in silico prediction of the variant is damaging by Mutation Taster2 tool. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796021	SCV005418865	pathogenic	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PS4_Moderate+PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000115111	SCV000591044	pathogenic	not provided		no assertion criteria provided	clinical testing	The APC p.Arg216X variant was identified in the literature in 20 of 4024 proband chromosomes (frequency: 0.005) from individuals or families with familial adenomatous polyposis (Friedl 2005, Gomez-Fernandez 2009, Kanter-Smoler 2008, Miyaki 1994 8187091, Plawski 2008, Rivera 2011, Schwarzova 2012, Strekova 2007). The variant was also identified in several databases: GeneInsight COGR (submitted by a clinical laboratory), Clinvitae (classified as “pathogenic” by Emory Genetics), UMD (40X, classified as “causal”), InSiGHT Colon Cancer Database (32X), Zhejiang Colon Cancer Database, and ClinVar (classified as pathogenic by GeneDX). The p.Arg216X variant leads to a premature stop codon at position 216, 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 familial adenomatous polyposis 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.