ClinVar Miner

Submissions for variant NM_020975.6(RET):c.134C>T (p.Ala45Val) (rs763526874)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568194 SCV000664523 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662783 SCV000785592 uncertain significance Multiple endocrine neoplasia, type 2a 2017-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000489446 SCV000577198 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing The A45V variant in the RET gene has previously been reported as a somatic variant in hepatocellular carcinoma but has not been reported in the germline (Ye et al., 2017). 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 A45V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000568194 SCV000822189 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000476072 SCV000543816 uncertain significance Multiple endocrine neoplasia, type 2 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 45 of the RET protein (p.Ala45Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs763526874, ExAC 0.01%). This variant has not been reported in the literature in individuals with RET-related disease. ClinVar contains an entry for this variant (Variation ID: 405538). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000662783 SCV000838365 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing

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