ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3387G>T (p.Leu1129Phe) (rs730881225)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159512 SCV000209467 uncertain significance not provided 2016-01-27 criteria provided, single submitter clinical testing This variant is denoted APC c.3387G>T at the cDNA level, p.Leu1129Phe (L1129F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Leu1129Phe 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 Phenylalanine share similar properties, this is considered a conservative amino acid substitution. APC Leu1129Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within a region responsible for down-regulation through a process mediated by direct ubiquitination as well as within the 15-aminio acid repeat beta-catenin binding domain (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 Leu1129Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000464483 SCV000552536 uncertain significance Familial adenomatous polyposis 1 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1129 of the APC protein (p.Leu1129Phe). 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. 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: "Possibly 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.
Ambry Genetics RCV000561698 SCV000672557 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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