ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3183_3187del (p.Lys1061_Gln1062insTer) (rs587779352)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162768 SCV000213245 pathogenic Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing The c.3183_3187delACAAA pathogenic mutation (also known as p.Q1062*), located in coding exon 15 of the APC gene, results from a deletion of 5 nucleotides at nucleotide positions 3183 to 3187. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation has been identified in numerous individuals and families from a variety of ethnic backgrounds with classic familial adenomatous polyposis (FAP), including some individuals with extra colonic manifestations including desmoid tumors, gastrointestinal cancers, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and epidermal cysts (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May;89:4452-6; Won YJ et al. J. Hum. Genet. 1999;44:103-8; González S et al. Cancer Genet. Cytogenet. 2005 Apr;158:70-4; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Friedl W & Aretz S. Hered. Cancer Clin. Pract. 2005 Sep;3:95-114; Plawski A & Slomski R. J. Appl. Genet. 2008;49:407-14; Fostira F et al. BMC Cancer. 2010 Jul;10:389; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J. Mol. Diagn. 2013 Jan;15:31-43; Papp J et al. Fam. Cancer. 2016 Jan;15(1):85-97; Dahl NA et al. J. Pediatr. Hematol. Oncol. 2016 07;38(5):e154-7). Of note, this alteration is also described as a truncation at codon 1061 or codon 1060, and as c.3221_3225delACAAA in the 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077987 SCV000226392 pathogenic not provided 2013-08-22 criteria provided, single submitter clinical testing
Invitae RCV000144562 SCV000253730 pathogenic Familial adenomatous polyposis 1 2020-10-07 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the APC gene (p.Gln1062*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1782 amino acids of the APC protein. This variant has been observed in several individuals affected with familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908). ClinVar contains an entry for this variant (Variation ID: 88913). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000077987 SCV000256968 pathogenic not provided 2020-07-29 criteria provided, single submitter clinical testing PVS1, PS4_Mod, PP4
GeneDx RCV000077987 SCV000293390 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing This deletion of five nucleotides is denoted APC c.3183_3187delACAAA at the cDNA level and p.Gln1062Ter (Q1062X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAA[delACAAA]GTGA. The deletion creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TGA), and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 1782 amino acids are no longer translated. APC c.3183_3187delACAAA has been observed in multiple individuals with Familial Adenomatous Polyposis (Aceto 2005, Plawski 2008, Gomez-Fernandez 2009, Rivera 2011, Papp 2015, Liu 2016, Zhang 2016, Khan 2017). This variant is considered pathogenic.
Counsyl RCV000144562 SCV000488338 pathogenic Familial adenomatous polyposis 1 2016-03-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077987 SCV000600078 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502016 SCV000694026 pathogenic Familial multiple polyposis syndrome 2019-10-28 criteria provided, single submitter clinical testing Variant summary: APC c.3183_3187delACAAA (p.Gln1062X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250490 control chromosomes (gnomAD). c.3183_3187delACAAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Inra_2015, Miyoshi_1992, Papp_2016). These data indicate that the variant is very likely to be associated with disease. 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
National Molecular Genetics Centre of Cancer Research,N.N. Alexandrov National Cancer Centre of Belarus RCV000144562 SCV000778310 pathogenic Familial adenomatous polyposis 1 2018-05-28 criteria provided, single submitter clinical testing This sequence change (c.3183_3187delACAAA) creates a stop codon (p.Gln1062*) in exon 16 of the APC mRNA.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000502016 SCV000781075 pathogenic Familial multiple polyposis syndrome 2016-11-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000077987 SCV000821693 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variation is a deletion of five nucleotides at position 1062 of the APC protein, resulting in the formation of new stop codon. Thus, a premature protein. This results in premature termination of protein synthesis and inactivation of one allele. This particular mutation has been described in international literature in patients with Familial adenomatous polyposis (PMID: 1316610, PMID: 8162022, PMID: 15771908). This mutation has been described in the mutation database ClinVar (Variation ID: 55683).
Mendelics RCV000144562 SCV000838100 pathogenic Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722012 SCV000853185 pathogenic Craniopharyngioma 2016-02-29 criteria provided, single submitter clinical testing This is a frameshift mutation in which 5 nucleotides are deleted between coding positions 3183 and 3187 and is predicted to shift the reading frame at codon 1061.
Color Health, Inc RCV000162768 SCV000905975 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000077987 SCV001446775 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000077987 SCV001450058 pathogenic not provided 2019-05-06 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000144562 SCV001499606 pathogenic Familial adenomatous polyposis 1 2020-04-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077987 SCV001500823 pathogenic not provided 2020-08-01 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144562 SCV000189853 pathogenic Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353466 SCV000591132 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Gln1062X variant has been described as a common hotspot mutation in the literature, with a founder effect in at least one population (from the Spanish Balearic Islands) (Fostira 2010, Gonzales 2005). In six studies it was identified in 36 of 4386 chromosomes (frequency: 0.008) from individuals or families with familial adenomatous polyposis or colorectal cancer (Aceto 2005, Fostira 2010, Gonzales 2005, Kerr 2012, Plawski 2008, Wallis 1999), and was absent in control chromosomes from these studies. The variant was also identified in several database searches, including: GeneInsight COGR (classified as pathogenic by a clinical laboratory), HGMD, UMD (208X as a “causal” variant), COSMIC, Clinvitae, InSiGHT Colon Cancer Database (191X), Zhejiang Colon Cancer Database, and the ClinVar Database (classified as pathogenic by Emory Genetics Laboratory, Pathway Genomics, and Ambry Genetics). The p.Gln1062X variant leads to a premature stop codon at position 1062, 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. Notably, this variant occurs in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000077987 SCV001744538 pathogenic not provided no assertion criteria provided clinical testing

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