ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.4888C>T (p.Arg1630Cys)

gnomAD frequency: 0.00001  dbSNP: rs549532374
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000467108 SCV000553516 likely benign DICER1-related tumor predisposition 2025-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571126 SCV000661940 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-04 criteria provided, single submitter clinical testing The p.R1630C variant (also known as c.4888C>T), located in coding exon 22 of the DICER1 gene, results from a C to T substitution at nucleotide position 4888. The arginine at codon 1630 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals with rhabdomyosarcoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; de Kock L et al. Lancet Oncol, 2016 11;17:e470). This amino acid position is not well 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 RCV001201143 SCV001372189 likely benign not specified 2019-07-01 criteria provided, single submitter curation ACMG criteria met: PM1, BS2, BP1
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000467108 SCV001737458 uncertain significance DICER1-related tumor predisposition 2021-03-29 criteria provided, single submitter clinical testing The DICER1 c.4888C>T (p.Arg1630Cys) missense change has a maximum subpopulation frequency of 0.005% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95562369-G-A?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. Although this variant occurs in a gene where missense variants are more likely to be damaging (PMID: 27535533), the variant lies at a residue that has a constrained coding region score of 0 and is not predicted to be more damaging based on methods described by Havrilla et al (PMID: 30531870). This variant has been reported in individuals with rhabdomyosarcoma and atypical teratoid/rhabdoid tumor (PMID: 26580448, internal data). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4 RCV000571126 SCV002533030 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-12 criteria provided, single submitter curation
Baylor Genetics RCV003476117 SCV004193310 uncertain significance Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome 2023-12-25 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001201143 SCV005872880 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing Classification criteria: BP4_supporting

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