ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7292G>A (p.Arg2431Lys) (rs879254262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237076 SCV000294005 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing This variant is denoted APC c.7292G>A at the cDNA level, p.Arg2431Lys (R2431K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in at least one colorectal carcinoma (Cancer Genome 2012). APC Arg2431Lys 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 Lysine share similar properties, this is considered a conservative amino acid substitution. APC Arg2431Lys occurs at a position that is conserved across species and is not located in a known functional 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 Arg2431Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463350 SCV000552447 uncertain significance Familial adenomatous polyposis 1 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2431 of the APC protein (p.Arg2431Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. 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: 246445). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000562107 SCV000667224 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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