Submissions for variant NM_000038.6(APC):c.4666dup (p.Thr1556fs)

dbSNP: rs587783031

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491894	SCV000579826	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The c.4666dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 4666, causing a translational frameshift with a predicted alternate stop codon (p.T1556Nfs*3). This mutation has been reported in two unrelated Italian polyposis patients (Gismondi V et al. Hum. Mutat. 1997;9(4):370-3), and a Spanish patient diagnosed with osteoma who had no family history of cancer (Rivera B et al. Ann Oncol. 2011 Apr;22(4):903-9). It was also observed in a two-year-old boy with a Gardner-associated fibroma, lumbar paraspinal desmoid and multiple other lesions; both parents tested negative for the mutation (Kiessling P et al. Cold Spring Harb. Mol. Case Stud. 2019 Apr;5(2)). Of note, this alteration is also designated as 4663insA in published literature. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000583680	SCV000691753	pathogenic	not provided	2023-12-12	criteria provided, single submitter	clinical testing	PM2, PS2_supporting, PVS1
National Molecular Genetics Centre of Cancer Research, N.N. Alexandrov National Cancer Centre of Belarus	RCV000656377	SCV000778309	pathogenic	Familial adenomatous polyposis 1	2018-05-30	criteria provided, single submitter	clinical testing	Detected in patient with clinical features of Gardner syndrome. Emory Genetics Laboratory Classification Definitions Pathogenic: a. Variants predicted to result in the loss of protein function in a gene for which this is a known mechanism of disease (may or may not have been previously reported in patients with disease) 1. frameshift (an insertion or deletion that is not a multiple of 3 nucleotides).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000656377	SCV000941363	pathogenic	Familial adenomatous polyposis 1	2023-04-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. 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. Experimental studies have shown that this premature translational stop signal affects APC function (PMID: 14633595). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 428112). This variant is also known as 4663insA. This premature translational stop signal has been observed in individuals with familial adenomatous polyposis (PMID: 9101302, 11852337, 17411426, 19029688, 20685668, 20924072, 21110124, 26511139). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1556Asnfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 amino acid(s) of the APC protein.
Color Diagnostics, LLC DBA Color Health	RCV000491894	SCV002053563	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 16 of the APC gene, creating a frameshift and 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 performed for this variant. This variant has been reported in individuals affected with more than 10 patients with familial adenomatous polyposis (PMID: 15024739, 17411426, 22987206, 16134147, 11852337, 18433509, 20223039, 20685668, 24750145, 30696621). 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.
Human Genetics Bochum, Ruhr University Bochum	RCV000656377	SCV002758617	pathogenic	Familial adenomatous polyposis 1	2021-12-08	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Myriad Genetics, Inc.	RCV000656377	SCV004044724	pathogenic	Familial adenomatous polyposis 1	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500725	SCV000591177	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Thr1556AsnfsX3 variant was identified in 18 of 4600 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, and was not identified in 150 control chromosomes from healthy individuals (Aceto 2005, Friedl 2005, Han 2011, Kanter-Smoler 2008, Kohoutova 2002, Liu 2007, Out 2015, Palacio_Rua 2014, Plawski 2008, Rivera 2011, Schwarzova 2013, Stekrova 2007, Vandrovcova 2004), however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in HGMD, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database” and UMD (7X as a un validated variant). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr1556AsnfsX3 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1556 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV005049571	SCV005684970	not provided	Malignant tumor of pancreas		no assertion provided	literature only