Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000705686 | SCV000834695 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 919 of the RET protein (p.Ala919Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 581770). 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: 10445857). 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 | RCV002440539 | SCV002749021 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-06 | criteria provided, single submitter | clinical testing | The p.A919P variant (also known as c.2755G>C), located in coding exon 16 of the RET gene, results from a G to C substitution at nucleotide position 2755. The alanine at codon 919 is replaced by proline, an amino acid with highly similar properties. In one paper, this alteration was shown to have low transforming activity in vitro (Iwashita T, et al. Oncogene 1999;18(26):3919-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV002485764 | SCV002789953 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2022-05-25 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004527752 | SCV004112166 | uncertain significance | RET-related disorder | 2023-04-13 | criteria provided, single submitter | clinical testing | The RET c.2755G>C variant is predicted to result in the amino acid substitution p.Ala919Pro. This variant with a second RET1 missense variant was reported in a metastatic lymph node from a female patient with familial medullary thyroid cancer (Iwashita T et al 1999. PubMed ID: 10445857). Functional studies indicate this variant may alter protein function (Iwashita T et al 1999. PubMed ID: 10445857; Iwashita T et al 1999. PubMed ID: 10445857). This variant was also reported as a somatic variant of uncertain significance in a diffuse leptomeningeal glioneuronal tumor sample (Table 1 in Manoharan et al. 2021. PubMed ID: 34493325). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43617418-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |