ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2261C>T (p.Thr754Met)

gnomAD frequency: 0.00009  dbSNP: rs181856591
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000202914 SCV000258170 uncertain significance Multiple endocrine neoplasia 2015-02-13 criteria provided, single submitter clinical testing
Counsyl RCV000410377 SCV000489733 uncertain significance Multiple endocrine neoplasia type 2B 2015-11-21 criteria provided, single submitter clinical testing
Counsyl RCV000411486 SCV000489734 uncertain significance Multiple endocrine neoplasia type 2A 2015-11-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000462996 SCV000543817 uncertain significance Multiple endocrine neoplasia, type 2 2024-01-21 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 754 of the RET protein (p.Thr754Met). This variant is present in population databases (rs181856591, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 135177). 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. 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 RCV000573705 SCV000674805 likely benign Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Sema4, Sema4 RCV000573705 SCV002529969 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-02 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002492438 SCV002787858 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2024-04-29 criteria provided, single submitter clinical testing
GeneDx RCV003151746 SCV003840662 uncertain significance not provided 2024-09-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (PMID: 24728327); This variant is associated with the following publications: (PMID: 24336963, 24728327, 14633923)
Baylor Genetics RCV003460858 SCV004208684 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-03-15 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000462996 SCV004838666 uncertain significance Multiple endocrine neoplasia, type 2 2024-08-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 754 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM RCV004771463 SCV005382284 uncertain significance Familial medullary thyroid carcinoma 2023-05-20 criteria provided, single submitter clinical testing The observed missense variant c.2261C>T (p.Thr754Met) in the RET gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Threonine at position 754 is changed to a Methionine changing protein sequence and it might alter its composition and physico- chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
ITMI RCV000121979 SCV000086189 not provided not specified 2013-09-19 no assertion provided reference population

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