ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2764C>T (p.Leu922Phe) (rs150543576)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491333 SCV000579925 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000546397 SCV000647265 uncertain significance Familial adenomatous polyposis 1 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 922 of the APC protein (p.Leu922Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs150543576, 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: 428176). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color RCV000491333 SCV000909255 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779717 SCV000916476 uncertain significance not specified 2018-01-29 criteria provided, single submitter clinical testing Variant summary: APC c.2764C>T (p.Leu922Phe) results in a non-conservative amino acid changelocated in the EB-1 binding(IPR009232) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 121162 control chromosomes in ExAC. The available data on variant occurrences in the general population are insufficient to allow any conclusion about clinical significance. To our knowledge, no occurrence of c.2764C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both of which classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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