ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.4475T>C (p.Met1492Thr)

gnomAD frequency: 0.00002  dbSNP: rs370947079
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Total submissions: 8
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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 RCV000654444 SCV005043095 likely benign DICER1-related tumor predisposition 2024-02-27 reviewed by expert panel curation The NM_177438.2:c.4475T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 1492 (p.Met1492Thr). 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). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.049; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1614146 alleles) with highest population minor allele frequencies of 0.00001334 (1/74954alleles) and 0.000002542 (3/1180050) in the African American and European (non-Finnish) populations, respectively (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.3.0; 02/27/2024)
Ambry Genetics RCV000561694 SCV000669331 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-10 criteria provided, single submitter clinical testing The p.M1492T variant (also known as c.4475T>C), located in coding exon 22 of the DICER1 gene, results from a T to C substitution at nucleotide position 4475. The methionine at codon 1492 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000654444 SCV000776338 uncertain significance DICER1-related tumor predisposition 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1492 of the DICER1 protein (p.Met1492Thr). This variant is present in population databases (rs370947079, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 483407). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics RCV000765192 SCV000896427 uncertain significance Euthyroid goiter; Rhabdomyosarcoma, embryonal, 2; DICER1-related tumor predisposition 2018-10-31 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000561694 SCV002533009 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-05 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003420012 SCV004117382 uncertain significance DICER1-related disorder 2023-03-21 criteria provided, single submitter clinical testing The DICER1 c.4475T>C variant is predicted to result in the amino acid substitution p.Met1492Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 3 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/14-95562782-A-G) and is interpreted as uncertain significance in CLinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/483407/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV004569211 SCV005059433 uncertain significance Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome 2024-03-27 criteria provided, single submitter clinical testing
GeneDx RCV004773012 SCV005385820 uncertain significance not provided 2024-02-05 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; Has not been previously published as pathogenic or benign to our knowledge

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