Submissions for variant NM_000038.6(APC):c.3786T>C (p.Tyr1262=)

gnomAD frequency: 0.00009  dbSNP: rs147411334

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534465	SCV000252920	likely benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000423289	SCV000512072	benign	not specified	2015-06-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000491700	SCV000579794	likely benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800523	SCV000600089	benign	not provided	2020-12-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491700	SCV000681633	likely benign	Hereditary cancer-predisposing syndrome	2016-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423289	SCV001361425	benign	not specified	2019-01-29	criteria provided, single submitter	clinical testing	Variant summary: APC c.3786T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9e-05 in 276270 control chromosomes (gnomAD). The observed variant frequency is approximately 1.27 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3786T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000491700	SCV002533925	likely benign	Hereditary cancer-predisposing syndrome	2021-09-04	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001800523	SCV004042231	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000423289	SCV004243239	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354708	SCV001549390	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Tyr1262= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs147411334) “With Likely benign allele”, ClinVar (classified benign by GeneDx, and likely benign by Invitae, Ambry Genetics, Color Genomics Inc. and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and in control databases in 25 of 276270 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24002 chromosomes (freq: 0.00004), Other in 3 of 6446 chromosomes (freq: 0.0005), Latino in 5 of 34372 chromosomes (freq: 0.0001), European Non-Finnish in 14 of 125934 chromosomes (freq: 0.0001), European Finnish in 1 of 25772 chromosomes (freq: 0.00004), and South Asian in 1 of 30756 chromosomes (freq: 0.00003) while not observed in the Ashkenazi Jewish and East Asian populations. The p.Tyr1262= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.