ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1907C>T (p.Thr636Met)

gnomAD frequency: 0.00001  dbSNP: rs1035958105
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000463920 SCV000543837 uncertain significance Multiple endocrine neoplasia, type 2 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 636 of the RET protein (p.Thr636Met). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 25725622). ClinVar contains an entry for this variant (Variation ID: 405553). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 25725622). 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 RCV000570272 SCV000674859 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-07 criteria provided, single submitter clinical testing The p.T636M variant (also known as c.1907C>T), located in coding exon 11 of the RET gene, results from a C to T substitution at nucleotide position 1907. The threonine at codon 636 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a woman diagnosed with sporadic medullary thyroid cancer at age 78 years of age. Functional assays measuring cell growth and proliferation, contact inhibition, and cell migration showed levels somewhat higher than wild-type, which the authors described as low-grade transforming potential (Silva AL et al. Endocrine. 2015 Jun;49(2):366-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000709117 SCV000838391 uncertain significance Multiple endocrine neoplasia type 2A 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV001778963 SCV002015658 uncertain significance not provided 2023-07-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect: increased cell growth, migration, and proliferation, as well as decreased contact inhibition compared to wildtype; however, these effects were reportedly milder than the p.C634R positive control (PMID: 25725622); This variant is associated with the following publications: (PMID: 14633923, 30755392, 26319365, 30446652, 26678667, 27311873, 25725622, 35264596)
PreventionGenetics, part of Exact Sciences RCV004529586 SCV004110532 uncertain significance RET-related disorder 2023-03-15 criteria provided, single submitter clinical testing The RET c.1907C>T variant is predicted to result in the amino acid substitution p.Thr636Met. This variant has been reported in an individual with thyroid cancer (Silva et al. 2015. PubMed ID: 25725622). This variant has been reported in a presumed unaffected parent from an exome trio analysis (Table S2, Ji et al. 2019. PubMed ID: 30755392). In vitro experimental studies suggest this variant may impact protein function (Silva et al. 2015. PubMed ID: 25725622). This variant is reported in 3 of ~248,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-43609955-C-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405553/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV004567960 SCV005054210 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-01-14 criteria provided, single submitter clinical testing

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