ClinVar Miner

Submissions for variant NM_177438.2(DICER1):c.5126A>G (p.Asp1709Gly) (rs1555366979)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546662 SCV000658329 uncertain significance DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 2017-03-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1709 of the DICER1 protein (p.Asp1709Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with pleuropulmonary blastoma (PPB) as a mosaic variant although it is uncertain whether it was originated from the germline or not (PMID: 26925222). This variant also has been reported as a somatic variant in tumors from individuals affected with DICER1-related conditions (PMID: 22187960, 26555935, 27459524). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This missense change is located at a functionally conserved metal-binding residue (p.Asp1709) within the RNase IIIb domain of the DICER1 protein (PMID: 22187960, 26408257, 23132766) and a significant number of previously reported DICER1 missense mutations have been found at this residue (PMID: 22187960, 26475046, 24839956, 24676357). These observations suggest that a novel missense substitution affecting this residue may affect protein function, but experiments have not been done to test this possibility. In summary, this variant is a rare missense change affecting a residue shown to be important for protein function. In the absence of additional genetic and/or functional data, it has been classified as a Variant of Uncertain Significance.

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