ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1396A>G (p.Met466Val) (rs781364007)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677766 SCV000803922 uncertain significance Colorectal cancer 2018-04-21 no assertion criteria provided clinical testing
Ambry Genetics RCV000565633 SCV000667703 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000484801 SCV000564564 uncertain significance not provided 2016-10-04 criteria provided, single submitter clinical testing This variant is denoted APC c.1396A>G at the cDNA level, p.Met466Val (M466V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met466Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met466Val occurs at a position that is conserved across species and is located in the armadillo region (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 Met466Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000694091 SCV000822518 uncertain significance Familial adenomatous polyposis 1 2018-05-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 466 of the APC protein (p.Met466Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs781364007, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 418009). 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: "Benign"; 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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