Submissions for variant NM_000038.6(APC):c.2805C>A (p.Tyr935Ter)

dbSNP: rs137854575

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844610	SCV000058709	pathogenic	Familial multiple polyposis syndrome	2014-01-27	criteria provided, single submitter	clinical testing	The Tyr935X variant in APC has been reported in >20 individuals with FAP, segreg ated with disease in at least 12 affected family members (see references), and w as absent from large population studies (rs137854575). This nonsense variant le ads to a premature termination codon at position 935, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the APC gene is an established disease mechanism in individuals with FAP. In summary, this v ariant meets our criteria to be classified as pathogenic (http://pcpgm.partners. org/LMM) based upon segregation studies and absence from controls.
Ambry Genetics	RCV000129305	SCV000184067	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-22	criteria provided, single submitter	clinical testing	The p.Y935* pathogenic mutation (also known as c.2805C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 2805. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This pathogenic mutation has been reported in numerous families with Familial Adenomatous Polyposis (FAP) (van der Luijt RB et al. Hum. Mutat.1997;9:7-16; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9). 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. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202012	SCV000209507	pathogenic	not provided	2023-03-10	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; Observed in multiple unrelated patients with Familial Adenomatous Polyposis (FAP) referred for genetic testing at GeneDx and in published literature (Fodde et al., 1992; Won et al., 1999; Aceto et al., 2005; Kim et al., 2005; Agatea et al., 2015; Simbolo et al., 2015; Khan et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26917275, 16134147, 1324223, 26300997, 28533537, 27978560, 29753700, 18199528, 16292097, 35189564, 35142982, 26792031, 10083733, 16088911)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210151	SCV000266007	pathogenic	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000848	SCV000552450	pathogenic	Familial adenomatous polyposis 1	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr935*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1909 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 FAP and thyroid cancer and familial adenomatous polyposis (FAP) (PMID: 1324223, 1944466, 8381579, 8990002, 10083733, 10094547, 10713886, 11748858, 11933206, 12173026, 15024739, 15108288, 16088911, 16317745, 17411426, 19793053, 20685668, 20924072, 26300997). ClinVar contains an entry for this variant (Variation ID: 810). 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, internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202012	SCV000600067	pathogenic	not provided	2023-07-11	criteria provided, single submitter	clinical testing	The APC c.2805C>A (p.Tyr935*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in several individuals and families affected with FAP (PMID: 35142982 (2022), 26300997 (2015), 23970361 (2013), 20924072 (2011), 12173026 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129305	SCV000686914	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 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 multiple families and individuals affected with colorectal polyposis and cancer (PMID: 1324223, 8381579, 10083733, 10094547, 10713886, 11748858, 12173026, 15024739, 16088911, 17411426, 19444466, 20685668, 20924072). This variant also has been reported in individuals affected with osteoma (PMID: 19444466) and hepatoblastoma (PMID: 16317745). 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.
Fulgent Genetics, Fulgent Genetics	RCV000763542	SCV000894355	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
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202012	SCV001450173	pathogenic	not provided	2016-01-14	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000000848	SCV002104258	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000000848	SCV004043966	pathogenic	Familial adenomatous polyposis 1	2023-05-05	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	RCV000000848	SCV004196444	pathogenic	Familial adenomatous polyposis 1	2023-10-16	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000000848	SCV004808043	pathogenic	Familial adenomatous polyposis 1	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000000848	SCV000020998	pathogenic	Familial adenomatous polyposis 1	1992-08-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202012	SCV000256955	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202012	SCV000591118	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202012	SCV001955736	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202012	SCV001963500	pathogenic	not provided		no assertion criteria provided	clinical testing