Submissions for variant NM_000038.6(APC):c.4533C>T (p.Leu1511=)

gnomAD frequency: 0.00007  dbSNP: rs150089434

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535616	SCV000282757	likely benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001705237	SCV000516191	likely benign	not provided	2021-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26010451)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001705237	SCV000600103	likely benign	not provided	2023-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568570	SCV000667297	likely benign	Hereditary cancer-predisposing syndrome	2015-01-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000568570	SCV000681671	likely benign	Hereditary cancer-predisposing syndrome	2017-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418393	SCV000694055	likely benign	not specified	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: APC c.4533C>T 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 4.8e-05 in 250356 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 7.1e-05 in the gnomAD database. The observed variant frequency in the Non-Finnish European subpopulation is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis (FAP) phenotype (7.1e-05), suggesting that the variant is benign. In addition, the variant occurs in the North-western European subpopulation with an even higher frequency (i.e. 0.00012) further supporting a benign role. To our knowledge, no occurrence of c.4533C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000568570	SCV002534351	likely benign	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000418393	SCV004025064	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing