ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2477A>C (p.Tyr826Ser) (rs34617196)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205464 SCV000261139 uncertain significance Multiple endocrine neoplasia, type 2 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 826 of the RET protein (p.Tyr826Ser). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs34617196, ExAC 0.02%). This variant has been reported in a family affected with medullary thyroid carcinoma and C-cell hyperplasia, however, the affected individuals also carried a pathogenic variant in the RET gene (PMID: 27099842). ClinVar contains an entry for this variant (Variation ID: 220530). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000411008 SCV000490097 uncertain significance Multiple endocrine neoplasia, type 2b 2016-11-08 criteria provided, single submitter clinical testing
Counsyl RCV000412172 SCV000490098 uncertain significance Multiple endocrine neoplasia, type 2a 2016-11-08 criteria provided, single submitter clinical testing
GeneDx RCV000679731 SCV000567961 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing The Y826S variant in the RET gene was observed in trans with the pathogenic RET variant V804M in a patient with medullary thyroid cancer who had both maternal and paternal family histories of thyroid cancer (Karrasch et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y826S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The Y826S variant occurs at a position that is not conserved and is located in the protein kinase domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider Y826S to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000679731 SCV000807028 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV001015653 SCV001176512 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing Insufficient evidence

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