Submissions for variant NM_000038.6(APC):c.694C>T (p.Arg232Ter)

dbSNP: rs397515734

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844606	SCV000058721	pathogenic	Familial multiple polyposis syndrome	2012-01-31	criteria provided, single submitter	clinical testing	The Arg232X nonsense variant has previously been reported as pathogenic in the l iterature. This variant has been identified as a germline change in at least 15 individuals with clinical features of Familial Adenomatous Polyposis syndrome (M iyoshi 1992, Olschwang 1997, Kraus 1998, Gavert 2002, Michils 2002, Bisgaard 200 4, Friedl 2005, Aceto 2005, De la Fuente 2007, Fostira 2010, Han 2011, Rivera 20 11) and in one individual with clinical diagnosis of Attenuated Familial Adenoma tous Polyposis (AFAP) (Rivera 2011). The presence of a heterozygous pathogenic v ariant in APC is consistent with a diagnosis of Familial Adenomatous Polyposis ( FAP) syndrome.
Invitae	RCV000035081	SCV000552617	pathogenic	Familial adenomatous polyposis 1	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg232*) 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: 1316610, 20223039, 20685668, 24735542). ClinVar contains an entry for this variant (Variation ID: 42248). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000486263	SCV000568266	pathogenic	not provided	2022-06-16	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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16134147, 20223039, 20649969, 20924072, 12173026, 9342373, 25525159, 12007223, 17963004, 1316610, 22886683, 9664575, 21110124, 15108286, 24033266, 26917275, 26900293, 26300997, 26446593, 29961768, 30897307, 31269945, 31447099)
Ambry Genetics	RCV000491782	SCV000579780	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-23	criteria provided, single submitter	clinical testing	The p.R232* pathogenic mutation (also known as c.694C>T), located in coding exon 6 of the APC gene, results from a C to T substitution at nucleotide position 694. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation is well described in the literature and has been reported in multiple individuals diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. 1992 May;89(10):4452-6; Friedl W and Aretz S. Hered. Cancer Clin. Pract. 2005 Sep;3(3):95-114; Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10; Zhang Y et al. Biochem. Biophys. Res. Commun. 2014 May;447(3):503-7; Simbolo M et al. Hered. Cancer Clin. Pract. 2015 Aug;13(1):18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000486263	SCV000691706	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PS4_moderate, PVS1
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000844606	SCV000781066	pathogenic	Familial multiple polyposis syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000035081	SCV000839877	pathogenic	Familial adenomatous polyposis 1	2017-12-04	criteria provided, single submitter	clinical testing	This c.694C>T (p.Arg232*) variant in the APC gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with familial adenomatous polyposis (PMID: 1316610, 8187091, 8730280, 8990002, 9664575, 9950360, 12007223, 12173026, 15108286, 16134147, 17963004, 20223039, 20649969, 20924072, 21110124, 23159591). The c.694C>T (p.Arg232*) variant in the APC gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486263	SCV000887548	pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763537	SCV000894350	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
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000486263	SCV001446595	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491782	SCV002053379	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 1316610, 1338764, 7524601, 7833149, 8381580, 10077047, 11668620, 12007223, 12010888, 12173026, 15108286, 17963004, 18433509, 19279422, 21110124, 23116752, 23159591) and a family affected with colorectal cancer and polyps (PMID: 24735542). 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.
MGZ Medical Genetics Center	RCV000035081	SCV002579302	pathogenic	Familial adenomatous polyposis 1	2021-09-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000035081	SCV004043981	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	RCV000035081	SCV004199488	pathogenic	Familial adenomatous polyposis 1	2023-10-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000486263	SCV000591048	pathogenic	not provided		no assertion criteria provided	clinical testing	The APC p.Arg232X variant was identified in the literature in 18 of 7060 proband chromosomes (frequency: 0.003) from individuals with familial adenomatous polyposis (Dobbie 1996, Fostira 2010, Friedle 2005, Han 2011, Kerr 2012, Michils 2002, Miyaki 1994, Miyoshi 1992, Olschwang 1993, Van der Luijt 1997, Wallis 1999); and was found to segregate with disease in one of the families studied, increasing the likelihood that it is pathogenic (Olschwang 1993). This variant was also identified in HGMD, “InSiGHT Colon Cancer Database”, and 66 times in UMD. The p.Arg232X variant leads to a premature stop codon at position 232, 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 is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000035081	SCV004808114	uncertain significance	Familial adenomatous polyposis 1	2024-03-29	flagged submission	clinical testing