Submissions for variant NM_000038.6(APC):c.2626C>T (p.Arg876Ter)

dbSNP: rs121913333

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002228900	SCV000253729	pathogenic	Familial adenomatous polyposis 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg876*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1968 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: 8187091, 12581900, 14961559, 17411426, 19029688, 20223039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216014). 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.
GeneDx	RCV000236362	SCV000293420	pathogenic	not provided	2021-08-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation 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: 14961559, 15108288, 17411426, 26446593, 26625971, 33294277, 29367705, 24651453, 25623536, 25025766, 25695693, 25832318, 7833931, 18433509, 19029688, 20223039, 8187091, 19347965, 12581900, 23159591, 25307848, 20007843, 17653897, 14729851, 27146902, 10646887)
Ambry Genetics	RCV000492041	SCV000579769	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-22	criteria provided, single submitter	clinical testing	The p.R876* pathogenic mutation (also known as c.2626C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2626. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been previously reported in multiple individuals with familial adenomatous polyposis (FAP) syndrome (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Ficari F et al. Br. J. Cancer, 2000 Jan;82:348-53; De Rosa M et al. Hum. Mutat., 2003 Jun;21:655-6; Mihalatos M et al. Cancer Genet. Cytogenet., 2003 Feb;141:65-70; Kanter-Smoler G et al. BMC Med, 2008 Apr;6:10; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2; Zhang S et al. Gene, 2016 Feb;577:187-92; Ciavarella M et al. Eur. J. Hum. Genet. 2018 03;26(3):387-395). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236362	SCV001133313	pathogenic	not provided	2018-11-23	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000185	SCV001156678	pathogenic	not specified	2018-09-07	criteria provided, single submitter	clinical testing	The APC c.2626C>T; p.Arg876Ter variant (rs121913333) is reported in the literature in multiple individuals and families affected with familial adenomatous polyposis (De Rosa 2003, Ficari 2000, Friedl 2005, Hashimoto 2015, Kanter-Smoler 2008, Lagarde 2010, Mihalatos 2003, Miyaki 1994, Stekrova 2007, Stella 1994). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 216014) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the APC gene. While this may not lead to nonsense-mediated decay, it is expected to truncate 1,968 amino acids and is predicted to result in a nonfunctional protein. Based on available information, this variant is considered to be pathogenic. References: De Rosa M et al. The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations. Hum Mutat. 2003 Jun;21(6):655-6. Ficari F et al. APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer. 2000 Jan;82(2):348-53. Friedl W and Aretz S. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Hashimoto T et al. Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. Histopathology. 2015 Nov;67(5):689-98. Kanter-Smoler G et al. Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families. BMC Med. 2008 Apr 24;6:10. Lagarde A et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. 2010 Oct;47(10):721-2. Mihalatos M et al. Novel mutations of the APC gene in familial adenomatous polyposis in Greek patients. Cancer Genet Cytogenet. 2003 Feb;141(1):65-70. 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. Stekrova J et al. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet. 2007 Apr 5;8:16. Stella A et al. Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. Hum Mol Genet. 1994 Sep;3(9):1687-8.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000236362	SCV001449781	pathogenic	not provided	2014-10-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236362	SCV002017607	pathogenic	not provided	2019-05-20	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002228900	SCV002512418	pathogenic	Familial adenomatous polyposis 1	2022-02-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate
Mayo Clinic Laboratories, Mayo Clinic	RCV000236362	SCV002522534	pathogenic	not provided	2021-04-07	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PS4_moderate, PVS1_strong
MGZ Medical Genetics Center	RCV002288811	SCV002580130	pathogenic	Familial adenomatous polyposis 1	2021-09-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236362	SCV004026012	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_SUP
Myriad Genetics, Inc.	RCV002228900	SCV004043990	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.
Database of Curated Mutations (DoCM)	RCV000438475	SCV000504996	likely pathogenic	Neoplasm of the large intestine	2015-07-14	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500904	SCV000591114	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Arg876X variant has not been previously identified by our laboratory, but has been reported and in the literature in 36 out of 6228 proband chromosomes in individuals with FAP, HNPCC, and sporadic colorectal carcinoma. It was not found in any of the 400 control chromosomes (Friedl, Aretz 2005, Goranova 2011, Albuquerque 2010, Liu 2007, Miyaki 1994, Powell 1992, Plawksi 2008, Dymerska 2010, Ruruuchi 2000, Albuquerque 2002, Olschwang 1997, Stekrova 2007, Scheel 2010). The variant leads to a premature stop codon at position 876 which is predicted to cause premature truncation of the protein product and loss of function. Loss of function of the APC gene is an established mechanism of familial adenomatous polyposis. In summary based on the above information, this variant is classified as pathogenic.