ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2342A>G (p.Gln781Arg) (rs377767416)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232536 SCV000290544 uncertain significance Multiple endocrine neoplasia, type 2 2019-09-15 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 781 of the RET protein (p.Gln781Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with multiple endocrine neoplasia type 2 (MEN2) as present in cis with a de novo variant in RET (p.Val804Met), but the two other family members also carrying this variant were asymptomatic (PMID: 23468374). It has also been reported in an unrelated individual and another family with two family members affected with medullary thyroid carcinoma (MTC) (PMID: 12072055, 28946813). ClinVar contains an entry for this variant (Variation ID: 24938). 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"). 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 RCV000988346 SCV001138030 benign Multiple endocrine neoplasia, type 2a 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000232536 SCV000042514 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only First family report, 2 have the mutation genotype: 2 MTC. Single French Individual report: MTC at 73 yr (PMID 28946813). Second family report, 2 with variant genotype: asymptomatic at 64 and 31 yr (PMID 23468374). In this second family, p.Q781R was also found in cis with another RET change, see c.[2342A>G;2410G>A].

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