ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1997A>G (p.Lys666Arg)

dbSNP: rs377767439
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001915699 SCV002185148 uncertain significance Multiple endocrine neoplasia, type 2 2021-07-22 criteria provided, single submitter clinical testing 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces lysine with arginine at codon 666 of the RET protein (p.Lys666Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with medullary thyroid cancer (MTC) (PMID: 25319874). ClinVar contains an entry for this variant (Variation ID: 549802). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Lys666 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15858153, 21678021, 21690267, 24569963, 26269449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
All of Us Research Program, National Institutes of Health RCV001915699 SCV005430366 uncertain significance Multiple endocrine neoplasia, type 2 2024-09-23 criteria provided, single submitter clinical testing

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