ClinVar Miner

Submissions for variant NM_000038.6(APC):c.688C>T (p.Arg230Cys) (rs587779805)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000758738 SCV000149026 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted APC c.688C>T at the cDNA level, p.Arg230Cys (R230C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in several tumors (COSMIC, Harismendy 2011). APC Arg230Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg230Cys occurs at a position that is conserved across species and located in a coiled coil domain within a Leucine-rich region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Arg230Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168032 SCV000218684 uncertain significance Familial adenomatous polyposis 1 2018-03-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 230 of the APC protein (p.Arg230Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 24599579). ClinVar contains an entry for this variant (Variation ID: 127316). 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: "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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115117 SCV000600141 uncertain significance not specified 2017-07-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565988 SCV000675859 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000565988 SCV000681831 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758738 SCV000887546 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115117 SCV000916497 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: APC c.688C>T (p.Arg230Cys) results in a non-conservative amino acid change located in the RecF/RecN/SMC N terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276902 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.688C>T has been reported in the literature as a confirmed somatic event in a different solid tumor samples Giannakis_2016, Harismendy_2011, pickering_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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