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]
Link to SEPIO compliant JSON-LD document

Variant: NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu)

CA390865100

477252 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f3166799-ec49-4d7b-984e-4918b817197d
Approved on: 2023-07-10
Published on: 2023-07-20

HGVS expressions

NM_177438.3:c.5259C>G
NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu)
NC_000014.9:g.95093993G>C
CM000676.2:g.95093993G>C
NC_000014.8:g.95560330G>C
CM000676.1:g.95560330G>C
NC_000014.7:g.94630083G>C
NG_016311.1:g.68430C>G
ENST00000343455.8:c.5259C>G
ENST00000393063.6:c.5259C>G
ENST00000526495.6:c.5259C>G
ENST00000556045.6:c.5259C>G
ENST00000675540.1:n.3004C>G
ENST00000675995.1:c.*3575C>G
ENST00000343455.7:c.5259C>G
ENST00000393063.5:c.5259C>G
ENST00000526495.5:c.5259C>G
ENST00000527414.5:c.5259C>G
ENST00000541352.5:c.5259C>G
ENST00000556045.5:c.1953C>G
NM_001195573.1:c.5259C>G
NM_001271282.2:c.5259C>G
NM_001291628.1:c.5259C>G
NM_030621.4:c.5259C>G
NM_177438.2:c.5259C>G
NM_001271282.3:c.5259C>G
NM_001291628.2:c.5259C>G
NM_001395677.1:c.5259C>G
NM_001395678.1:c.5259C>G
NM_001395679.1:c.5259C>G
NM_001395680.1:c.5259C>G
NM_001395682.1:c.5259C>G
NM_001395683.1:c.5259C>G
NM_001395684.1:c.5259C>G
NM_001395685.1:c.5259C>G
NM_001395686.1:c.4977C>G
NM_001395687.1:c.4854C>G
NM_001395688.1:c.4854C>G
NM_001395689.1:c.4854C>G
NM_001395690.1:c.4854C>G
NM_001395691.1:c.4692C>G
NM_001395697.1:c.3576C>G
NR_172715.1:n.5677C>G
NR_172716.1:n.5861C>G
NR_172717.1:n.5771C>G
NR_172718.1:n.5694C>G
NR_172719.1:n.5527C>G
NR_172720.1:n.5604C>G

Uncertain Significance

Met criteria codes 2
PM1_Supporting PM2_Supporting
Not Met criteria codes 15
PP4 PP1 PP3 PM5 PS2 PS4 PS3 PS1 BA1 BP2 BP4 BS2 BS4 BS3 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_177438.2:c.5259C>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 1753 (p.Asp1753Glu). 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). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 1.2.0; 07/10/2023)
Met criteria codes
PM1_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).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).
Not Met criteria codes
PP4
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
PP3
The computational predictor REVEL gives a score of 0.58, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
PM5
4 different missense variants, (c.5258A>G, p.Asp1753Gly; c.5257G>C, p.Asp1753His; c.5257G>T, p.Asp1753Tyr; c.5257G>A, p.Asp1753Asn), in the same codon have been reported in patients with DICER1 syndrome (PMIDs, ClinVar Variation ID, Internal lab contributors, etc]. However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The computational predictor REVEL gives a score of 0.58, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
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