ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7573C>T (p.Arg2525Cys) (rs774952444)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202809 SCV000257789 uncertain significance Familial multiple polyposis syndrome 2015-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000590375 SCV000292465 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted APC c.7573C>T at the cDNA level, p.Arg2525Cys (R2525C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in at least one patient with personal and family history of colorectal cancer (Chubb 2015). APC Arg2525Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Arg2525Cys occurs at a position that is conserved in mammals and is not located in a known functional domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Arg2525Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000476356 SCV000552520 uncertain significance Familial adenomatous polyposis 1 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2525 of the APC protein (p.Arg2525Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs774952444, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 218507). 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. 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 RCV000236933 SCV000600153 uncertain significance not specified 2017-06-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573374 SCV000667438 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000573374 SCV000681877 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590375 SCV000694120 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing

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