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)

CA390864547

1513387 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
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
More

Uncertain Significance

Met criteria codes 3
PM1_Supporting PM2_Supporting BP4
Not Met criteria codes 9
PP1 PP3 PM6 PS2 PM4 BA1 PVS1 BP7 BS1

Evidence Links 0

Expert Panel

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)
Met criteria codes
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).
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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