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

dbSNP: rs137854580

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002227979	SCV000261001	pathogenic	Familial adenomatous polyposis 1	2024-01-28	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. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). 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: 8381580, 9487968, 20223039, 20685668, 21779980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 824). 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	2022-05-03	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	2020-07-21	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; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12486240, 26650777, 31543384, 25525159, 20649969, 20223039, 18433509, 23263490, 9487968, 8381580, 12173026, 26613750, 27705013, 26917275, 26837502, 28135145, 28944238, 31118792)
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 Diagnostics, LLC DBA Color Health	RCV000491830	SCV000905882	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 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 individuals affected with familial adenomatous polyposis (PMID: 8381580, 9487968, 10077047, 12007223, 12010888, 12173026, 12486240, 15024739, 15951963, 18433509, 20223039, 20649969, 20685668, 20924072, 21779980, 23159591, 25590978). It has been shown that this variant segregates with familial adenomatous polyposis (PMID: 9487968). 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.
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.
Revvity Omics, Revvity	RCV000521676	SCV003815499	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002227979	SCV004018830	pathogenic	Familial adenomatous polyposis 1	2023-02-23	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499412	SCV004029863	pathogenic	Familial multiple polyposis syndrome	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: APC c.1495C>T (p.Arg499X) 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 was absent in 251260 control chromosomes. c.1495C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Mankaney_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35979026). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000204796	SCV004207139	pathogenic	Familial adenomatous polyposis 1	2023-04-05	criteria provided, single submitter	clinical testing
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
GenomeConnect - Invitae Patient Insights Network	RCV003483421	SCV004228871	not provided	APC-Associated Polyposis Disorders		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-07-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.