ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5225G>A (p.Arg1742His) (rs199775075)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119236 SCV000153981 uncertain significance Familial adenomatous polyposis 1 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1742 of the APC protein (p.Arg1742His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199775075, ExAC 0.02%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41508). 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.
Ambry Genetics RCV000163663 SCV000214234 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000034392 SCV000566133 uncertain significance not provided 2016-04-13 criteria provided, single submitter clinical testing This variant is denoted APC c.5225G>A at the cDNA level, p.Arg1742His (R1742H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Arg1742His 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 Arg1742His occurs at a position that is conserved across species and is located in the SAMP repeats and axin binding domain, as well as the 20-aa repeat B-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Arg1742His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000163663 SCV000681716 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-25 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034392 SCV000043131 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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