ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5224C>T (p.Arg1742Cys) (rs876658835)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221281 SCV000274599 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000487040 SCV000564576 uncertain significance not provided 2015-02-02 criteria provided, single submitter clinical testing This variant is denoted APC c.5224C>T at the cDNA level, p.Arg1742Cys (R1742C) 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 pathogenic or benign. APC Arg1742Cys 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 Arg1742Cys occurs at a position that is highly conserved across species and is located in the 20-amino acid repeat beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). 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 Arg1742Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000646381 SCV000768150 uncertain significance Familial adenomatous polyposis 1 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1742 of the APC protein (p.Arg1742Cys). 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 not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 230908). 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 disruptive, 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 RCV000221281 SCV000904857 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001151698 SCV001312863 uncertain significance APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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