ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2531G>A (p.Arg844Gln)

dbSNP: rs55947360
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205855 SCV000260662 uncertain significance Multiple endocrine neoplasia, type 2 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 844 of the RET protein (p.Arg844Gln). This variant is present in population databases (rs55947360, gnomAD 0.01%). This missense change has been observed in individual(s) with familial medullary thyroid carcinoma (PMID: 18058472, 24699901, 25425582, 30877234). ClinVar contains an entry for this variant (Variation ID: 24951). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 29625052). 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.
Ambry Genetics RCV000575953 SCV000674814 benign Hereditary cancer-predisposing syndrome 2023-06-21 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000662363 SCV000784750 uncertain significance Multiple endocrine neoplasia, type 2a 2017-01-25 criteria provided, single submitter clinical testing
Mendelics RCV000662363 SCV000838404 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV001292765 SCV001481411 uncertain significance Familial medullary thyroid carcinoma 2020-12-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001574570 SCV001801417 uncertain significance not provided 2023-07-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: RET kinase activity similar to wildtype (Huang et al., 2018); Observed in individuals with medullary thyroid cancer or breast cancer (Paszko et al., 2007; Guindalini et al., 2022) and co-observed with a pathogenic FH variant in an individual with pheochromocytoma (Ben Aim et al., 2019); This variant is associated with the following publications: (PMID: 20497437, 18058472, 26678667, 27014708, 21479187, 29590403, 25824727, 24699901, 9506724, 19469690, 29386230, 25425582, 34426522, 14633923, 29625052, 30877234, 35264596)
Mayo Clinic Laboratories, Mayo Clinic RCV001574570 SCV002541061 uncertain significance not provided 2021-04-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001574570 SCV002585215 uncertain significance not provided 2022-09-01 criteria provided, single submitter clinical testing RET: PS4:Moderate, PM2:Supporting, BS3:Supporting
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000662363 SCV003928100 uncertain significance Multiple endocrine neoplasia, type 2a 2023-04-03 criteria provided, single submitter clinical testing The RET c.2531G>A (p.Arg844Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however functional studies have demonstrated no damaging effect on RET function (PMID: 29625052). This variant has been reported in individuals with medullary thyroid cancer (PMID: 18058472) and pheochromocytoma (PMID: 35189708). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc. RCV000662363 SCV004018474 uncertain significance Multiple endocrine neoplasia, type 2a 2023-04-18 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV003466869 SCV004208661 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-10-13 criteria provided, single submitter clinical testing

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