ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5627G>T (p.Arg1876Met) (rs773201570)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217420 SCV000273390 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000237081 SCV000293813 uncertain significance not provided 2016-07-20 criteria provided, single submitter clinical testing This variant is denoted APC c.5627G>T at the cDNA level, p.Arg1876Met (R1876M) at the protein level, and results in the change of an Arginine to a Methionine (AGG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg1876Met 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 Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg1876Met occurs at a position that is conserved in mammals and is located within the 20-amino acid repeat beta-catenin down-regulating domain, the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconclusive regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Arg1876Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000560034 SCV000647601 uncertain significance Familial adenomatous polyposis 1 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 1876 of the APC protein (p.Arg1876Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant is present in population databases (rs773201570, ExAC 0.005%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 229993). 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 RCV000217420 SCV000687031 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-06 criteria provided, single submitter clinical testing

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