Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_177438.3(DICER1):c.5486C>G (p.Thr1829Arg)

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CA390864547

1513387 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5add8d04-86d5-4684-974e-be9c466316da

Approved on: 2023-07-10

Published on: 2023-07-20

HGVS expressions

NM_177438.3:c.5486C>G

NM_177438.3(DICER1):c.5486C>G (p.Thr1829Arg)

NC_000014.9:g.95091244G>C

CM000676.2:g.95091244G>C

NC_000014.8:g.95557581G>C

CM000676.1:g.95557581G>C

NC_000014.7:g.94627334G>C

NG_016311.1:g.71179C>G

ENST00000343455.8:c.5486C>G

ENST00000393063.6:c.5486C>G

ENST00000526495.6:c.5486C>G

ENST00000556045.6:c.*203C>G

ENST00000675540.1:n.3231C>G

ENST00000675995.1:c.*3802C>G

ENST00000343455.7:c.5486C>G

ENST00000393063.5:c.5486C>G

ENST00000526495.5:c.5486C>G

ENST00000527414.5:c.5486C>G

ENST00000527416.2:n.79C>G

ENST00000527554.2:n.179C>G

ENST00000541352.5:c.5365-135C>G

ENST00000556045.5:c.2180C>G

NM_001195573.1:c.5365-135C>G

NM_001271282.2:c.5486C>G

NM_001291628.1:c.5486C>G

NM_030621.4:c.5486C>G

NM_177438.2:c.5486C>G

NM_001271282.3:c.5486C>G

NM_001291628.2:c.5486C>G

NM_001395677.1:c.5486C>G

NM_001395678.1:c.5486C>G

NM_001395679.1:c.5486C>G

NM_001395680.1:c.5486C>G

NM_001395682.1:c.5486C>G

NM_001395683.1:c.5486C>G

NM_001395684.1:c.5486C>G

NM_001395685.1:c.5486C>G

NM_001395686.1:c.5204C>G

NM_001395687.1:c.5081C>G

NM_001395688.1:c.5081C>G

NM_001395689.1:c.5081C>G

NM_001395690.1:c.5081C>G

NM_001395691.1:c.4919C>G

NM_001395697.1:c.3803C>G

NR_172715.1:n.5904C>G

NR_172716.1:n.6088C>G

NR_172717.1:n.5998C>G

NR_172718.1:n.5921C>G

NR_172719.1:n.5754C>G

NR_172720.1:n.5957C>G

Uncertain Significance

PM1_Supporting PM2_Supporting BP4

PP1 PP3 PM6 PS2 PM4 BA1 PVS1 BP7 BS1

Evidence Links 0

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.3:c.5486C>G variant in DICER1 is a missense variant predicted to cause substitution of threonine by arginine at amino acid 1829 (p.Thr1829Arg). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.347, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). Due to conflicting evidence, this variant is classified as a variant of unknown significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_supporting, PM2_supporting, BP4. (Bayesian points 1; VCEP specifications version 1.2.0; 07/10/2023)

PM1_Supporting

This variant occurs in the RNase IIIb domain, which is a hotspot for missense variants associated with DICER1-related neoplasms (Heravi-Moussavi et al. 2012. PubMed ID: 22187960; Foulkes et al. 2014. PubMed ID: 25176334; Chen et al. 2018. PubMed ID: 31893257).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).

BP4

The computational predictor REVEL gives a score of 0.347, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4).

PP1