ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5593C>G (p.Leu1865Val) (rs1064794887)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480341 SCV000570159 uncertain significance not provided 2016-05-06 criteria provided, single submitter clinical testing This variant is denoted APC c.5593C>G at the cDNA level, p.Leu1865Val (L1865V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Leu1865Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Leu1865Val occurs at a position that is conserved across species and is located in the 20-aa repeat beta-catenin down-regulating domain as well as SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Leu1865Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000554585 SCV000647598 uncertain significance Familial adenomatous polyposis 1 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1865 of the APC protein (p.Leu1865Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 421068). 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: "Tolerated"; 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.

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