ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7088A>G (p.Lys2363Arg) (rs587779806)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115119 SCV000149028 uncertain significance not provided 2015-06-23 criteria provided, single submitter clinical testing This variant is denoted APC c.7088A>G at the cDNA level, p.Lys2363Arg (K2363R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys2363Arg 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 Arginine share similar properties, this is considered a conservative amino acid substitution. APC Lys2363Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the basic domain and the Ser-rich region (Azzopardi 2008, UniProt) In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Lys2363Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000233413 SCV000282811 uncertain significance Familial adenomatous polyposis 1 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 2363 of the APC protein (p.Lys2363Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs587779806, ExAC 0.003%) but has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 127317). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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