ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6775A>G (p.Lys2259Glu) (rs763707129)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225815 SCV000282803 uncertain significance Familial adenomatous polyposis 1 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 2259 of the APC protein (p.Lys2259Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs763707129, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 236634). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000482077 SCV000568047 uncertain significance not provided 2015-09-24 criteria provided, single submitter clinical testing This variant is denoted APC c.6775A>G at the cDNA level, p.Lys2259Glu (K2259E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys2259Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys2259Glu occurs at a position that is conserved across species and is located within the Basic domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Lys2259Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000582672 SCV000687093 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000225815 SCV000784743 uncertain significance Familial adenomatous polyposis 1 2017-11-13 criteria provided, single submitter clinical testing

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