ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.184G>A (p.Val62Ile)

gnomAD frequency: 0.00002  dbSNP: rs746671039
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000654380 SCV000776273 uncertain significance DICER1-related tumor predisposition 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 62 of the DICER1 protein (p.Val62Ile). This variant is present in population databases (rs746671039, gnomAD 0.007%). This missense change has been observed in individual(s) with corticotropinoma and/or rhabdomyosarcoma (PMID: 27050224, 27819237, 32714280). ClinVar contains an entry for this variant (Variation ID: 543572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 80%. 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 RCV001013380 SCV001173959 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-10 criteria provided, single submitter clinical testing The p.V62I variant (also known as c.184G>A), located in coding exon 2 of the DICER1 gene, results from a G to A substitution at nucleotide position 184. The valine at codon 62 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a pediatric patient diagnosed with rhabdosarcoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This alteration was also detected in a Brazilian patient diagnosed with Cushing's disease with corticotropinoma (Martínez de LaPiscina I et al. Front Endocrinol (Lausanne), 2020 Jul;11:433). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV001200980 SCV001371950 likely benign not specified 2019-07-01 criteria provided, single submitter curation ACMG criteria met: BS1, BP4
GeneDx RCV003128683 SCV003805550 uncertain significance not provided 2022-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with rhabdomyosarcoma as well as a child with Cushing's disease and a corticotropinoma whose tumor did not demonstrate loss of heterozygosity or a second DICER1 variant (Zhang et al., 2015; Martinez de LaPiscina et al., 2020); This variant is associated with the following publications: (PMID: 27819237, 26580448, 27050224, 28748527, 32714280)

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