ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8162G>A (p.Arg2721His) (rs587780606)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122808 SCV000166065 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2721 of the APC protein (p.Arg2721His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587780606, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 135723). 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.
Ambry Genetics RCV000218426 SCV000276416 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000479454 SCV000572792 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing This variant is denoted APC c.8162G>A at the cDNA level, p.Arg2721His (R2721H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or benign polymorphism. However, it has been reported as a somatic variant in colorectal and ovarian tumors (Crobach 2014, Crobach 2016). APC Arg2721His 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 Histidine share similar properties, this is considered a conservative amino acid substitution. APC Arg2721His occurs at a position that is not conserved and is located in 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 Arg2721His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000218426 SCV000904044 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing

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