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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_177438.2(DICER1):c.5465A>T (p.Asp1822Val)

CA10586400

254350 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 47c2c6a7-8144-418e-b4d0-69c01b152e08
Approved on: 2024-08-27
Published on: 2024-09-16

HGVS expressions

NM_177438.2:c.5465A>T
NM_177438.2(DICER1):c.5465A>T (p.Asp1822Val)
NC_000014.9:g.95091265T>A
CM000676.2:g.95091265T>A
NC_000014.8:g.95557602T>A
CM000676.1:g.95557602T>A
NC_000014.7:g.94627355T>A
NG_016311.1:g.71158A>T
ENST00000529720.2:c.5465A>T
ENST00000531162.7:c.5465A>T
ENST00000674628.2:c.5465A>T
ENST00000675540.2:c.*2115A>T
ENST00000696733.1:c.*87A>T
ENST00000696734.1:c.*120A>T
ENST00000696735.1:n.2452A>T
ENST00000696736.1:c.5465A>T
ENST00000696920.1:n.5728A>T
ENST00000696921.1:n.6571A>T
ENST00000696922.1:n.8396A>T
ENST00000696923.1:c.*120A>T
ENST00000696924.1:c.*87A>T
ENST00000696925.1:n.8396A>T
ENST00000343455.8:c.5465A>T
ENST00000393063.6:c.5465A>T
ENST00000526495.6:c.5465A>T
ENST00000556045.6:c.*182A>T
ENST00000675540.1:c.3210A>T
ENST00000675995.1:c.*3781A>T
ENST00000343455.7:c.5465A>T
ENST00000393063.5:c.5465A>T
ENST00000526495.5:c.5465A>T
ENST00000527414.5:c.5465A>T
ENST00000527416.2:n.58A>T
ENST00000527554.2:n.158A>T
ENST00000541352.5:c.5365-156A>T
ENST00000556045.5:c.2159A>T
NM_001195573.1:c.5365-156A>T
NM_001271282.2:c.5465A>T
NM_001291628.1:c.5465A>T
NM_030621.4:c.5465A>T
NM_001271282.3:c.5465A>T
NM_001291628.2:c.5465A>T
NM_177438.3:c.5465A>T
NM_001395677.1:c.5465A>T
NM_001395678.1:c.5465A>T
NM_001395679.1:c.5465A>T
NM_001395680.1:c.5465A>T
NM_001395682.1:c.5465A>T
NM_001395683.1:c.5465A>T
NM_001395684.1:c.5465A>T
NM_001395685.1:c.5465A>T
NM_001395686.1:c.5183A>T
NM_001395687.1:c.5060A>T
NM_001395688.1:c.5060A>T
NM_001395689.1:c.5060A>T
NM_001395690.1:c.5060A>T
NM_001395691.1:c.4898A>T
NM_001395697.1:c.3782A>T
NR_172715.1:n.5883A>T
NR_172716.1:n.6067A>T
NR_172717.1:n.5977A>T
NR_172718.1:n.5900A>T
NR_172719.1:n.5733A>T
NR_172720.1:n.5936A>T

Likely Pathogenic

Met criteria codes 5
PS4_Moderate PM2_Supporting PP3 PM1_Supporting PS3_Supporting
Not Met criteria codes 8
BS3 BS4 BS1 BA1 PS2 PS1 PM6 PVS1

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 1.3.0

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.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Asp1822Val showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University) (PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592) (PM1_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.954) (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1.3.0; 08/27/2024)
Met criteria codes
PS4_Moderate
3 points; Reported in 2 individuals with PPB (Brenneman et al. 2015. PMID: 26925222; 2 points); Reported in a proband with PPB (4y) and their parent with thyroid cysts (30y) (Family 11, Slade et al. 2011. PMID: 21266384; 1 point).
PM2_Supporting
Absent in gnomAD. Coverage is >20X.
PP3
REVEL=0.954; Splice AI Donor Gain Δ0.56 and Donor Loss Δ0.26; MaxEntScan cryptic donor GT site 64 (63?)nt upstream of 3’ ss, cryptic site 7.07 (up from 0) and native site 5.64 (unchanged)
PM1_Supporting
Missense variant in Rnase IIIb domain (p.Y1682 – p.S1846)
PS3_Supporting
Wu et al. 2018. PhD Thesis. "DICER1 syndrome: assays, associations and models" - Evaluated via in vitro cleavage assay per table 2.1; table 3.1; table 3.2 and 6.3 cleavage products = “Delayed to no 5p and 3p”; AKA Mutation 33; No reported paired somatic mutations identified yet.
Not Met criteria codes
BS3
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
BS1
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
PS2
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
PM6
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
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