Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564342 | SCV000674852 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-14 | criteria provided, single submitter | clinical testing | The p.N763I variant (also known as c.2288A>T), located in coding exon 13 of the RET gene, results from an A to T substitution at nucleotide position 2288. The asparagine at codon 763 is replaced by isoleucine, an amino acid with dissimilar properties. In one study examining physicochemical properties (changes in size, charge, polarity and hydrophobicity) and protein accessibility, this alteration is predicted to be neutral (George Priya Doss C et al. Mol Biosyst 2014 Mar; 10(3):421-36). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in association with MEN2 based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. |
| Invitae | RCV001064605 | SCV001229515 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-01-12 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 763 of the RET protein (p.Asn763Ile). This variant is present in population databases (rs199882293, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 41840). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Biesecker Lab/Clinical Genomics Section, |
RCV000034770 | SCV000043475 | variant of unknown significance | not provided | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Uncertain significance. |