ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2162G>A (p.Arg721Gln)

gnomAD frequency: 0.00001  dbSNP: rs1356141763
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneKor MSA RCV000708757 SCV000822196 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001205883 SCV001377163 uncertain significance Multiple endocrine neoplasia, type 2 2023-05-23 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 584563). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 721 of the RET protein (p.Arg721Gln).
GeneDx RCV001545206 SCV001764488 uncertain significance not provided 2023-07-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal or family history of breast/ovarian or other cancers (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 14633923)
Fulgent Genetics, Fulgent Genetics RCV002485780 SCV002792704 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2021-09-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000708757 SCV003911393 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-30 criteria provided, single submitter clinical testing The p.R721Q variant (also known as c.2162G>A), located in coding exon 12 of the RET gene, results from a G to A substitution at nucleotide position 2162. The arginine at codon 721 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.
Baylor Genetics RCV003460990 SCV004208637 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-10-25 criteria provided, single submitter clinical testing

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