ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8138T>C (p.Met2713Thr) (rs1479889029)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527165 SCV000647756 uncertain significance Familial adenomatous polyposis 1 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2713 of the APC protein (p.Met2713Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Integrated Genetics/Laboratory Corporation of America RCV000779731 SCV000916496 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: APC c.8138T>C (p.Met2713Thr) results in a non-conservative amino acid change located in the EB-1 binding 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 4.1e-06 in 246116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8138T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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