Submissions for variant NM_000038.6(APC):c.637C>T (p.Arg213Ter)

dbSNP: rs587781392

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129233	SCV000183988	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	clinical testing	The p.R213* pathogenic mutation (also known as c.637C>T), located in coding exon 5 of the APC gene, results from a C to T substitution at nucleotide position 637. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in multiple patients with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May 15;89(10):4452-6; Garcia-Lozano JR et al. Genet. Test. 2005 Spring;9(1):37-40; Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep 15;3(3):95-114); Stekrova J et al. BMC Med. Genet. 2007 Apr;8:16; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Morcrette G et al. Oncoimmunology Mar;8:e1583547; de Oliveira JC et al. Cancer Med, 2019 05;8:2114-2122). This pathogenic mutation has also been reported as a de novo mutation in one FAP patient who had over 1000 polyps (Kanter-Smoler G et al. BMC Med. 2008 Apr 24;6:10). 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.
GeneDx	RCV000202175	SCV000209567	pathogenic	not provided	2024-02-12	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 (gnomAD); This variant is associated with the following publications: (PMID: 1316610, 26659639, 25525159, 15024739, 11960572, 15857185, 22790147, 22987206, 27087319, 15300853, 26917275, 26138249, 25248397, 25986922, 26681312, 29419868, 20685668, 20223039, 29367705, 31069152, 11933206, 17411426, 10094547, 34259353, 33309985, 34897210)
Mayo Clinic Laboratories, Mayo Clinic	RCV000202175	SCV000257022	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Invitae	RCV002512529	SCV000282795	pathogenic	Familial adenomatous polyposis 1	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg213*) 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 and colon cancer (PMID: 1316610, 10094547, 17411426, 20223039, 20685668, 26681312). ClinVar contains an entry for this variant (Variation ID: 140952). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763535	SCV000894348	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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825611	SCV000966956	pathogenic	Familial multiple polyposis syndrome	2018-04-17	criteria provided, single submitter	clinical testing	The p.Arg213X variant in APC has been reported in >15 individuals with APC-assoc iated cancers (Miyoshi 1992, Giarola 1999, Stekrova 2006, Friedl 2005, Garcia-L azano 2005, Lagarde 2010, Susswein 2016) and was absent from large population st udies. This variant has been reported as a somatic variant in >90 tumor samples from various cancer types, including colorectal cancer (The Catalogue of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic). This variant has also been reported in ClinVar (Variant ID: 140952). This nonsense variant leads to a premature termination codon at position 213, which is predicted to lead to a tr uncated or absent protein. Heterozygous loss of function of the APC gene is an e stablished disease mechanism in individuals with familial adenomatous polyposis (FAP). In summary, this variant meets criteria to be classified as pathogenic fo r FAP in an autosomal dominant manner based upon predicted impact to the protein , presence in affected individuals, and absence in the general population. ACMG/ AMP Criteria applied: PVS1; PS4; PM2.
Myriad Genetics, Inc.	RCV002512529	SCV004044002	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	RCV002512529	SCV005056070	pathogenic	Familial adenomatous polyposis 1	2024-03-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353439	SCV000591043	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Arg213X variant was identified in 17 of 3498 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Friedl 2005, Giarola 1999, Kanter-Smoler 2008, Kohoutova 2002, Miyoshi 1992, Rivera 2011, Stekrova 2007, Vandrovcova 2004) and was not identified in 206 control chromosomes from healthy individuals (Kohoutova 2002, Stekrova 2007). The variant was also identified HGMD, COSMIC, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, the ClinVar database (classified as a pathogenic variant by Ambry Genetics), GeneInsight (1X, classified as “pathogenic”) and UMD (97X as a unclassified variant). The p.Arg213X variant leads to a premature stop codon at position 213, 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. Furthermore, this position has been shown to cause a very severe phenotype with early onset of the disease (Vandrovcova 2004). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.