ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1495C>T (p.Arg499Ter) (rs137854580)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204796 SCV000261001 pathogenic Familial adenomatous polyposis 1 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg499*) in the APC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 8381580, 9487968, 20685668, 20223039, 21779980). ClinVar contains an entry for this variant (Variation ID: 824). Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000204796 SCV000487892 pathogenic Familial adenomatous polyposis 1 2015-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491830 SCV000579777 pathogenic Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing The p.R499* pathogenic mutation (also known as c.1495C>T), located in coding exon 11 of the APC gene, results from a C to T substitution at nucleotide position 1495. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been described in many patients and families with familial adenomatous polyposis (FAP) (Olschwang S et al. Am. J. Hum. Genet. 1993 Feb;52:273-9; Friedl W et al. Hered Cancer Clin Pract 2005 Sep;3:95-114; Kanter-Smoler G et al. BMC Med 2008 Apr;6:10; Fostira F et al. BMC Cancer 2010 Jul;10:389; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2; Tsukanov AS et al. Russ J Genet. 2017 53(3):369-375). In one study of 136 Spanish classic FAP families, there appeared to be an association with desmoid tumors in patients who carried mutations in codon 499 (Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9). 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.
GeneDx RCV000521676 SCV000617335 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted APC c.1495C>T at the cDNA level and p.Arg499Ter (R499X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in patients and families with classical Familial Adenomatous Polyposis (Eccles 1997, Kanter-Smoler 2008, Fostira 2010, Marabelli 2016, Yurgelun 2017) and is considered pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000499412 SCV000781071 pathogenic Familial multiple polyposis syndrome 2016-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491830 SCV000905882 pathogenic Hereditary cancer-predisposing syndrome 2020-02-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000521676 SCV001133301 pathogenic not provided 2019-06-28 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.
OMIM RCV000000867 SCV000021017 pathogenic Gardner syndrome 1997-11-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353679 SCV000591076 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The APC p.Arg499* variant was identified in 20 of 4340 proband chromosomes (frequency: 0.005) from individuals or families with Familial Adenomatous Polyposis (Olschwang 1993, Friedl 2005, Lagarde 2010 20685668, Jarry 2011). The variant was identified in dbSNP (rs137854580) as “with pathogenic, uncertain significance allele”, ClinVar (interpreted as "pathogenic" by Invitae, Ambry Genetics and 7 others ), LOVD 3.0 (observed 33x) and UMD-LSDB (observed 35x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1495C>T variant leads to a premature stop codon at position 499, 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 meets our laboratory’s criteria to be classified as pathogenic.
Yale Center for Mendelian Genomics,Yale University RCV000204796 SCV000784635 pathogenic Familial adenomatous polyposis 1 2015-11-27 no assertion criteria provided literature only

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