ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3182T>C (p.Leu1061Pro) (rs536486113)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569228 SCV000674816 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000662784 SCV000785593 uncertain significance Multiple endocrine neoplasia, type 2a 2017-09-27 criteria provided, single submitter clinical testing
Invitae RCV000198421 SCV000255054 uncertain significance Multiple endocrine neoplasia, type 2 2015-04-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1061 of the RET protein (p.Leu1061Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has been reported in the literature in two individuals and a single family affected with Hirschsprung disease (PMID: 10484767). In a large consanguineous family, two children affected with total colonic aganglionosis were homozygous carriers for this variant while their heterozygous parents were asymptomatic. A third affected family member was heterozygous for this missense change. This variant is present in population databases (no rsID, <0.01%). Experimental studies have shown that this missense change disrupts the binding of RET to the IRS-1, SHC, and FRS2 proteins, leading to defects in downstream pathway activation (PMID: 11313948, 10465268, 10484767, 11390647). However, these studies were done using a constitutively activated form of RET that contains the pathogenic mutation Cys634Arg. The clinical significance of this data is therefore unknown. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change that has been seen in affected and unaffected family members, and is present in the general population. Although experimental studies suggest that this missense variant may be deleterious, the impact of this change on protein function is still uncertain. Therefore, this sequence change has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454885 SCV000540180 uncertain significance not specified 2016-12-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in a consanguinous family in the homozygous state in siblings and heterozygous state in a cousin with Hirschprung's disease. It has not been seen in individuals with MEN2A. It was found to partially inhibit the Shc-RET interaction by in vitro studies, which affects the ability of RET to transmit downstream signals. This variant is classified in ClinVar with 1 star as VUS by Invitae. The variant has a Max MAF of 0.009% in ExAC (1 allele) and 0.003% in gnomAD (1 allele).

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