ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1366C>T (p.Leu456Phe) (rs876660195)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214194 SCV000277408 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000590719 SCV000693994 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The APC c.1366C>T (p.Leu456Phe) variant located in the Armadillo-like helical domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed. The variant of interest was not observed in 120344 control chromosomes (ExAC). The variant of interest has not been, to our knowledge, reported in affected individuals via publications, although a clinical diagnostic laboratory cites the variant with a classification of "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000799782 SCV000939461 uncertain significance Familial adenomatous polyposis 1 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 456 of the APC protein (p.Leu456Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. 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: 233102). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.

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