ClinVar Miner

Submissions for variant NM_000038.6(APC):c.775C>T (p.Arg259Trp) (rs762117133)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465724 SCV000552762 uncertain significance Familial adenomatous polyposis 1 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 259 of the APC protein (p.Arg259Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs762117133, 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: 411556). 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 RCV000572577 SCV000676367 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000572577 SCV000681886 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-06 criteria provided, single submitter clinical testing
Counsyl RCV000465724 SCV000786061 uncertain significance Familial adenomatous polyposis 1 2018-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779741 SCV000916515 uncertain significance not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: The variant, APC c.775C>T (p.Arg259Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245776 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.775C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
True Health Diagnostics RCV000572577 SCV000693494 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-25 no assertion criteria provided clinical testing

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