Evidence Repository
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_030621.4(DICER1):c.878_881del (p.Arg293fs)

CA10586464

254355 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b6047466-f62a-4f0c-845a-8fe2dba71e1c
Approved on: 2022-05-18
Published on: 2022-07-08

HGVS expressions

NM_030621.4:c.878_881del
NM_030621.4(DICER1):c.878_881del (p.Arg293fs)
NC_000014.9:g.95126603_95126606del
CM000676.2:g.95126603_95126606del
NC_000014.8:g.95592940_95592943del
CM000676.1:g.95592940_95592943del
NC_000014.7:g.94662693_94662696del
NG_016311.1:g.35818_35821del
ENST00000343455.8:c.878_881del
ENST00000393063.6:c.878_881del
ENST00000526495.6:c.878_881del
ENST00000532939.3:c.878_881del
ENST00000556045.6:c.878_881del
ENST00000674628.1:c.878_881del
ENST00000675995.1:c.878_881del
ENST00000343455.7:c.878_881del
ENST00000393063.5:c.878_881del
ENST00000526495.5:c.878_881del
ENST00000527414.5:c.878_881del
ENST00000541352.5:c.878_881del
NM_001195573.1:c.878_881del
NM_001271282.2:c.878_881del
NM_001291628.1:c.878_881del
NM_177438.2:c.878_881del
NM_001271282.3:c.878_881del
NM_001291628.2:c.878_881del
NM_177438.3:c.878_881del
NM_001395677.1:c.878_881del
NM_001395678.1:c.878_881del
NM_001395679.1:c.878_881del
NM_001395680.1:c.878_881del
NM_001395682.1:c.878_881del
NM_001395683.1:c.878_881del
NM_001395684.1:c.878_881del
NM_001395685.1:c.878_881del
NM_001395686.1:c.596_599del
NM_001395687.1:c.473_476del
NM_001395688.1:c.473_476del
NM_001395689.1:c.473_476del
NM_001395690.1:c.473_476del
NM_001395691.1:c.311_314del
NM_001395692.1:c.878_881del
NM_001395693.1:c.878_881del
NM_001395694.1:c.878_881del
NM_001395695.1:c.878_881del
NM_001395696.1:c.473_476del
NM_001395697.1:c.-691_-688del
NM_001395698.1:c.473_476del
NM_001395699.1:c.878_881del
NM_001395700.1:c.878_881del
NR_172715.1:n.1092_1095del
NR_172716.1:n.1223_1226del
NR_172717.1:n.1390_1393del
NR_172718.1:n.1390_1393del
NR_172719.1:n.1223_1226del
NR_172720.1:n.1223_1226del
NM_177438.3(DICER1):c.878_881del (p.Arg293fs)
More

Pathogenic

Met criteria codes 4
PS4_Supporting PP4 PVS1 PM2_Supporting
Not Met criteria codes 9
BS3 BS1 BP2 PS2 PS3 BA1 PP1 PM1 PM6

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.878_881del (p.Arg293fs) variant in DICER1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 7/27 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant received a total of 1 phenotype point across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting, PMID: 26925222). This individual was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, PMID: 26925222). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PS4_Supporting, PP4, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 1; 02/11/2022)
Met criteria codes
PS4_Supporting
Germline variant in child with PPB Type II; inherited (Study ID 37 Table S3, S5, S6) – high specificity. 1 pt for proband with high-specificity phenotype (PMID: 26925222, NCI, IPPBR, Ambry)
PP4
Hotspot second hit variant identified in proband's PPB was c.5425G>A (p.G1809R) (PMID: 26925222)
PVS1
Predicted to undergo NMD, stop codon 5’ of p.P1850; (p.Arg293IlefsTer4)
PM2_Supporting
Absent from gnomAD 2.1.1 and 3.1.1 (non-cancer) with >20x coverage
Not Met criteria codes
BS3
No studies identified.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
PS3
No studies identified.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
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
Curation History
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