ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1462C>T (p.Leu488Phe) (rs587779782)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766427 SCV000148978 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted APC c.1462C>T at the cDNA level, p.Leu488Phe (L488F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has been observed in at least one individual with breast cancer (Tung 2015). APC Leu488Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Armadillo region (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Leu488Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475656 SCV000552463 uncertain significance Familial adenomatous polyposis 1 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 488 of the APC protein (p.Leu488Phe). 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: 127277). 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: "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.
Ambry Genetics RCV000574797 SCV000667281 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000574797 SCV000681464 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000115069 SCV000731361 uncertain significance not specified 2017-01-12 criteria provided, single submitter clinical testing The p.Leu488Phe variant in APC has not been previously reported in individuals w ith APC-associated polyposis or in large population studies. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Leu4 88Phe variant is uncertain.

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