ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3191T>C (p.Met1064Thr)

gnomAD frequency: 0.00002  dbSNP: rs149513065
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000557293 SCV000658476 uncertain significance Multiple endocrine neoplasia, type 2 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1064 of the RET protein (p.Met1064Thr). This variant is present in population databases (rs149513065, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 7581377, 14633923, 27525386). ClinVar contains an entry for this variant (Variation ID: 161359). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 9047383, 9502784). 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 RCV000569531 SCV000674853 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-24 criteria provided, single submitter clinical testing The p.M1064T variant (also known as c.3191T>C), located in coding exon 20 of the RET gene, results from a T to C substitution at nucleotide position 3191. The methionine at codon 1064 is replaced by threonine, an amino acid with similar properties. This variant has previously been reported in individuals affected with Hirschsprung disease (So MT et al. PLoS ONE 2011 Dec; 6(12):e28986; Attié T et al. Hum. Mol. Genet. 1995 Aug; 4(8):1381-6; Jannot AS et al. Eur. J. Hum. Genet. 2012 Sep; 20(9):917-20; Garcia-Barceló M et al. Clin Chem, 2004 Jan;50:93-100), as well as medullary thyroid cancer and pheochromocytoma (Sherman S et al. Cancer 2016 Dec;122(24):3856-3864; Ambry internal data). However, this variant has been detected in multiple individuals with no reported features of RET-associated disease (Ambry internal data). Functional studies using co-transfection with a constitutively activated MEN2A form of RET have shown this variant has minimal biological effect (Pelet A et al. J. Clin. Invest. 1998 Mar; 101(6):1415-23). Another study evaluated the effects of this alteration on binding various domains of the adaptor protein Shc, and found that p.M1064T binds three domains equally well as wild-type; but demonstrates a 30-40% reduction in binding affinity for the PTB domain of Shc (JLorenzo MJ et al. Oncogene 1997 Feb; 14(7):763-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Sema4, Sema4 RCV000569531 SCV002527906 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-31 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002505137 SCV002814519 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2022-04-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462057 SCV004208641 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-01-19 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV003480062 SCV004225232 uncertain significance not provided 2022-03-18 criteria provided, single submitter clinical testing PP3
All of Us Research Program, National Institutes of Health RCV000557293 SCV004828166 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 1064 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). Functional studies have reported conflicting evidence of this variant's impact on transforming and kinase activity (PMID: 9047383, 9502784). This variant has been reported in an individual affected with medullary thyroid cancer (PMID: 27525386) and individuals affected with Hirschsprung disease (PMID: 14633923, 22174939, 22395866). This variant has been identified in 4/251476 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.
CSER _CC_NCGL, University of Washington RCV000148784 SCV000190522 uncertain significance Aganglionic megacolon 2014-06-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.