ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8141G>A (p.Arg2714His) (rs747362422)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457741 SCV000552655 uncertain significance Familial adenomatous polyposis 1 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2714 of the APC protein (p.Arg2714His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs747362422, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411478). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000759449 SCV000564586 uncertain significance not provided 2017-04-02 criteria provided, single submitter clinical testing This variant is denoted APC c.8141G>A at the cDNA level, p.Arg2714His (R2714H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). APC Arg2714His was observed at an allele frequency of 0.002472% (3/121364) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. APC Arg2714His occurs at a position that is not conserved and is located within the EB1 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 Arg2714His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571502 SCV000667220 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Mendelics RCV000457741 SCV000838160 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759449 SCV000888775 uncertain significance not provided 2019-08-10 criteria provided, single submitter clinical testing
Color RCV000571502 SCV000903029 likely benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000759449 SCV001154488 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing

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