Submissions for variant NM_000038.6(APC):c.2778T>C (p.Ser926=) (rs371526966)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220698	SCV000275426	likely benign	Hereditary cancer-predisposing syndrome	2015-04-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507103	SCV000600063	likely benign	not specified	2017-01-15	criteria provided, single submitter	clinical testing
Invitae	RCV000530592	SCV000647267	likely benign	Familial adenomatous polyposis 1	2017-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000507103	SCV000728926	likely benign	not specified	2017-06-21	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.
Color	RCV000220698	SCV000904122	likely benign	Hereditary cancer-predisposing syndrome	2018-02-05	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000507103	SCV000916508	likely benign	not specified	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: APC c.2778T>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 2.9e-05 in 276802 control chromosomes and was observed exclusively in the African subpopulation of the gnomAD database at a frequency of 0.00033. This frequency is approximately 5-fold above the maximal expected allele frequency for a pathogenic variant in Familial Adenomatous Polyposis, suggesting the variant is a benign polymorphism found in populations of African ancestry. To our knowledge, no occurrence of c.2778T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.