ClinVar Miner

Submissions for variant NM_020630.4(RET):c.1996A>G (p.Lys666Glu) (rs143795581)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Institute,ARUP Laboratories RCV000021838 SCV000042504 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only First family report, 8 with variant genotype: 3 MTC (57 yr, 49 yr, 35 yr), 2 C-cell hyperplasia (34 yr, 53 yr). Second family report, 2 with variant genotype: MTC (64 yr). Third family report, 5 with variant genotype: Pheo (35 yr). Single individual report: MTC at 64 yr (PMID 21690267).
Ambry Genetics RCV000567780 SCV000674767 pathogenic Hereditary cancer-predisposing syndrome 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
CSER_CC_NCGL; University of Washington Medical Center RCV000148771 SCV000190508 likely benign Medullary thyroid carcinoma 2014-06-01 no assertion criteria provided research
Invitae RCV000021838 SCV000834776 likely pathogenic Multiple endocrine neoplasia, type 2 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 666 of the RET protein (p.Lys666Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with medullary thyroid cancer (MTC) in a family (PMID: 15858153). It has also been reported in unrelated individuals with unilateral MTC (PMID: 21690267, 15858153) or pheochromocytoma (PMID: 15858153). ClinVar contains an entry for this variant (Variation ID: 24931). Experimental studies have shown that this missense change results in a gain-of-function RET activity with an increased RET phosphorylation activity, and increased transformation potential in cell culture (PMID: 21690267). A different missense substitution at this codon (p.Lys666Asn) has been determined to be pathogenic (PMID: 27673361, 20103606, 26269449, 20103606). This suggests that the lysine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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