ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3191T>C (p.Met1064Thr) (rs149513065)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557293 SCV000658476 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1064 of the RET protein (p.Met1064Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs149513065, ExAC 0.03%). This variant has been observed in two members of a family affected with Hirschsprung disease, but a third family member that carried this variant was unaffected (PMID: 7581377). This variant has also been reported in an additional unrelated individual affected with Hirschsprung disease (PMID: 14633923), as well as in a study cohort of individuals affected with medullary thyroid cancer (PMID: 27525386). ClinVar contains an entry for this variant (Variation ID: 161359). An experimental study has shown that this missense change does not significantly affect the transforming capacity, neuronal differentiation capability, or catalytic activity of the RET51 isoform (PMID: 9502784). However, an additional experimental study found that this missense change demonstrates a reduced capacity to bind to the Shc PTB domain located at tyrosine 1062, resulting in a 50% reduction in Shc phosphorylation compared to the wildtype RET51 isoform, which could potentially lead to reduced recruitment of other downstream signaling phosphoproteins into the RET complex (PMID: 9047383). The clinical significance of this last finding is unclear. 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 2016-06-20 criteria provided, single submitter clinical testing Insufficient evidence
CSER _CC_NCGL, University of Washington RCV000148784 SCV000190522 uncertain significance Hirschsprung disease 2014-06-01 no assertion criteria provided research

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