ClinVar Miner

Submissions for variant NM_000038.6(APC):c.647G>A (p.Arg216Gln) (rs76685252)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168256 SCV000218927 uncertain significance Familial adenomatous polyposis 1 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 216 of the APC protein (p.Arg216Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs76685252, ExAC 0.02%). This variant has been reported in individuals affected with colorectal cancer (PMID: 18199528, 28135145). ClinVar contains an entry for this variant (Variation ID: 188275). 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 tolerated, 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.
Illumina Clinical Services Laboratory,Illumina RCV000364207 SCV000451984 likely benign APC-Associated Polyposis Disorders 2018-03-06 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000480784 SCV000568267 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing This variant is denoted APC c.647G>A at the cDNA level, p.Arg216Gln (R216Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in at least one individual with colorectal adenomas and in an individual undergoing germline inherited cancer testing (Azzopardi 2008, Minde 2011, Mandelker 2017). APC Arg216Gln was not observed in large population cohorts (Lek 2016). APC Arg216Gln is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Arg216Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563625 SCV000672497 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Other data supporting pathogenic classification
Counsyl RCV000168256 SCV000785219 uncertain significance Familial adenomatous polyposis 1 2017-06-06 criteria provided, single submitter clinical testing
Mendelics RCV000168256 SCV000838066 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000563625 SCV000911013 likely benign Hereditary cancer-predisposing syndrome 2016-06-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480784 SCV001133356 uncertain significance not provided 2019-08-24 criteria provided, single submitter clinical testing

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