ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.4740G>T (p.Gln1580His)

gnomAD frequency: 0.00003  dbSNP: rs369465519
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen RCV000468344 SCV002599114 likely benign DICER1-related tumor predisposition 2022-10-25 reviewed by expert panel curation The NM_177438.2:c.4740G>T variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 1580 (p.Gln1580His). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (BS3_Supporting; Wu 2018, McGill University). The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function. In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BS3_Supporting. (Bayesian Points: -2; VCEP specifications version 1.1.0; 10/25/2022)
Labcorp Genetics (formerly Invitae), Labcorp RCV000468344 SCV000553622 likely benign DICER1-related tumor predisposition 2024-01-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574285 SCV000661849 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-14 criteria provided, single submitter clinical testing The p.Q1580H variant (also known as c.4740G>T), located in coding exon 22 of the DICER1 gene, results from a G to T substitution at nucleotide position 4740. The glutamine at codon 1580 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with a seminoma diagnosed at age 32 (Slade I et al. J. Med. Genet., 2011 Apr;48:273-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 RCV001201139 SCV001372183 likely benign not specified 2019-07-01 criteria provided, single submitter curation ACMG criteria met: PP3, BS3, BP1
GeneDx RCV002461208 SCV002757409 uncertain significance not provided 2022-05-23 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; Observed in an individual with a seminoma (Slade 2011); This variant is associated with the following publications: (PMID: 24136150, 21266384, 24708902, 23547758, 33158809, 29762508, 28748527)

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