ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5628G>T (p.Arg1876Ser) (rs1064794942)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481170 SCV000570265 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing This variant is denoted APC c.5628G>T at the cDNA level, p.Arg1876Ser (R1876S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg1876Ser 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 Serine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg1876Ser occurs at a position that is conserved in mammals and is located in the 20-amino acid repeat B-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Arg1876Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562178 SCV000667476 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000562178 SCV000681753 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Invitae RCV000814031 SCV000954421 uncertain significance Familial adenomatous polyposis 1 2018-09-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 1876 of the APC protein (p.Arg1876Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. 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: 421150). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.

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