Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000654570 | SCV000776464 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2025-01-14 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 117 of the RET protein (p.Pro117His). This variant is present in population databases (rs763295929, gnomAD 0.002%). 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: 543735). 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. |
| Ambry Genetics | RCV001020483 | SCV001181969 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-13 | criteria provided, single submitter | clinical testing | The p.P117H variant (also known as c.350C>A), located in coding exon 3 of the RET gene, results from a C to A substitution at nucleotide position 350. The proline at codon 117 is replaced by histidine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2-causing variant in this gene 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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. |
| Fulgent Genetics, |
RCV002493057 | SCV002784701 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2021-10-25 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000654570 | SCV004815190 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with histidine at codon 117 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute lymphoblastic leukemia (PMID: 32084258). This variant has been identified in 3/250788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV004568472 | SCV005054202 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2024-01-22 | criteria provided, single submitter | clinical testing |