Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167414 | SCV000218269 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-02 | criteria provided, single submitter | clinical testing | The p.T451M variant (also known as c.1352C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1352. The threonine at codon 451 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000654555 | SCV000776449 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 451 of the RET protein (p.Thr451Met). This variant is present in population databases (rs774092678, gnomAD 0.006%). 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: 187665). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226229 | SCV003923157 | uncertain significance | not specified | 2023-03-03 | criteria provided, single submitter | clinical testing | Variant summary: RET c.1352C>T (p.Thr451Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1352C>T in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| All of Us Research Program, |
RCV000654555 | SCV004829006 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-08-13 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 451 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 3/251460 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 | RCV004567348 | SCV005054171 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2024-03-24 | criteria provided, single submitter | clinical testing |