ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2417A>G (p.Tyr806Cys)

dbSNP: rs377767419
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000798052 SCV000937647 uncertain significance Multiple endocrine neoplasia, type 2 2024-07-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 806 of the RET protein (p.Tyr806Cys). This variant is present in population databases (rs377767419, gnomAD 0.001%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 in whom it occurs on the same chromosome with the pathogenic RET p.Val804Met variant (PMID: 25759805). ClinVar contains an entry for this variant (Variation ID: 24942). 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: 10679286). 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 RCV004668740 SCV005162614 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-30 criteria provided, single submitter clinical testing The p.Y806C variant (also known as c.2417A>G), located in coding exon 14 of the RET gene, results from an A to G substitution at nucleotide position 2417. The tyrosine at codon 806 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in a MEN 2B family but was found to co-occur with a RET p.V804M mutation (Kihara M et al. Eur Thyroid J, 2014 Dec;3:272-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health RCV000798052 SCV005430381 uncertain significance Multiple endocrine neoplasia, type 2 2024-06-11 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 806 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown this variant individually does not increase transforming ability in transfected cells (PMID: 10679286). his variant has been reported in an individual affected with multiple endocrine neoplasia type 2; this individual also carried a pathogenic co-variant in the RET gene that could explain the observed phenotype (PMID: 10076558). This variant has been identified in 1/236534 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.

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