Submissions for variant NM_000038.6(APC):c.8306A>G (p.Lys2769Arg)

dbSNP: rs878853475

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650541	SCV000282842	uncertain significance	Familial adenomatous polyposis 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2769 of the APC protein (p.Lys2769Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 236655). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000572285	SCV000667449	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	The p.K2769R variant (also known as c.8306A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 8306. The lysine at codon 2769 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420830	SCV001623219	uncertain significance	not specified	2021-05-03	criteria provided, single submitter	clinical testing	Variant summary: APC c.8306A>G (p.Lys2769Arg) results in a conservative amino acid change located in the EB-1 binding domain (IPR009232) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250994 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8306A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001753683	SCV002005328	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29338072, 25801821)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753683	SCV004220655	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). To the best of our knowledge, this variant has not been reported in the germline state in individuals with an APC related disease. However, it has been reported as a somatic variant in a colon cancer tumor sample (PMID: 29338072 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.