Submissions for variant NM_000038.6(APC):c.1488A>T (p.Thr496=) (rs9282599)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084609	SCV000166015	benign	Familial adenomatous polyposis 1	2020-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164173	SCV000214791	likely benign	Hereditary cancer-predisposing syndrome	2014-07-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Clinical Services Laboratory,Illumina	RCV000318991	SCV000451989	likely benign	APC-Associated Polyposis Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508123	SCV000600044	likely benign	not specified	2016-11-15	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000164173	SCV000681468	benign	Hereditary cancer-predisposing syndrome	2016-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587584	SCV000693998	benign	not provided	2017-06-09	criteria provided, single submitter	clinical testing	Variant summary: The APC c.1488A>T (p.Thr496Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 55/121488 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.006028 (52/8626). This frequency is about 84 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587584	SCV000887507	benign	not provided	2018-03-11	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000587584	SCV001746823	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000587584	SCV001830129	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001356780	SCV001552041	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Thr496= variant was identified in 1 of 338 proband chromosomes (frequency: 0.01) from individuals or families with colorectal cancer, and was not identified in 244 control chromosomes from healthy individuals (Chang 2016, Chen 2006). The variant was also identified in dbSNP (ID: rs9282599) as “With Likely benign allele”, ClinVar (classified as benign by Invitae, Color Genomics and Integrated Genetics/Laboratory Corporation of America; as likely benign by Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, LOVD 3.0 (Probably does not affect function), or Zhejiang Colon Cancer Database (2X). The variant was not identified in GeneInsight-COGR, Cosmic, or UMD-LSDB databases. The variant was identified in control databases in 123 of 277014 chromosomes (1 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 122 of 18852 chromosomes (freq: 0.01), Finnish in 1 of 25786 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, and South Asian populations. The p.Thr496= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics,Academic Medical Center	RCV000508123	SCV001920993	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000587584	SCV001954828	likely benign	not provided		no assertion criteria provided	clinical testing