Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166496 | SCV000217295 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-27 | criteria provided, single submitter | clinical testing | The p.R525W variant (also known as c.1573C>T), located in coding exon 8 of the RET gene, results from a C to T substitution at nucleotide position 1573. The arginine at codon 525 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a Chinese family with a history of medullary thyroid carcinoma; however, a second RET gene mutation, p.S891A , was also detected in this family. The p.S891A mutation segregated with disease in the family whereas those who only carried p.R525W were unaffected. Furthermore, a cell proliferation assay assessing p.R525W alone showed no oncogenic effect (Qi XP et al. Oncotarget. 2015 Oct;6(32):33993-4003; Qi XP et al. BMC Cancer. 2021 Apr;21:369). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000476004 | SCV000543813 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 525 of the RET protein (p.Arg525Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC), however a different pathogenic RET variant was also identified in these individuals. This variant has also been reported in an unaffected individual (PMID: 25425582, 26356818). ClinVar contains an entry for this variant (Variation ID: 135191). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 26356818). 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. |
| Fulgent Genetics, |
RCV002492439 | SCV002803823 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2024-04-23 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004528837 | SCV004107313 | uncertain significance | RET-related disorder | 2023-03-04 | criteria provided, single submitter | clinical testing | The RET c.1573C>T variant is predicted to result in the amino acid substitution p.Arg525Trp. This variant was previously reported in five individuals from one family; three individuals were unaffected, while two individuals (who also harbored a second RET variant) presented with familial medullary thyroid carcinoma associated with cutaneous amyloidosis (Qi et al. 2015. PubMed ID: 26356818). This variant is reported in 0.0057% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43607597-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Gene |
RCV004719703 | SCV005325393 | uncertain significance | not provided | 2023-05-30 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Co-observed in trans with a RET pathogenic variant in individuals with medullary thyroid cancer from a single family (Qi et al., 2015); Published functional studies demonstrate: cellular proliferation similar to wildtype, slightly increased Akt phosphorylation, inhibition of RET glycosylation and dimerization, and aberrant cellular localization (Qi et al., 2015); This variant is associated with the following publications: (PMID: 14633923, 24728327, 25425582, 33827484, 26356818) |
| ITMI | RCV000121998 | SCV000086209 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |