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

Variant: NM_177438.3(DICER1):c.5465A>G (p.Asp1822Gly)

CA390864594

429125 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 85a9bd30-cffd-49d0-bdc3-ddca494a51fc
Approved on: 2024-10-22
Published on: 2024-11-13

HGVS expressions

NM_177438.3:c.5465A>G
NM_177438.3(DICER1):c.5465A>G (p.Asp1822Gly)
NC_000014.9:g.95091265T>C
CM000676.2:g.95091265T>C
NC_000014.8:g.95557602T>C
CM000676.1:g.95557602T>C
NC_000014.7:g.94627355T>C
NG_016311.1:g.71158A>G
ENST00000529720.2:c.5465A>G
ENST00000531162.7:c.5465A>G
ENST00000674628.2:c.5465A>G
ENST00000675540.2:c.*2115A>G
ENST00000696733.1:c.*87A>G
ENST00000696734.1:c.*120A>G
ENST00000696735.1:n.2452A>G
ENST00000696736.1:c.5465A>G
ENST00000696920.1:n.5728A>G
ENST00000696921.1:n.6571A>G
ENST00000696922.1:n.8396A>G
ENST00000696923.1:c.*120A>G
ENST00000696924.1:c.*87A>G
ENST00000696925.1:n.8396A>G
ENST00000343455.8:c.5465A>G
ENST00000393063.6:c.5465A>G
ENST00000526495.6:c.5465A>G
ENST00000556045.6:c.*182A>G
ENST00000675540.1:c.3210A>G
ENST00000675995.1:c.*3781A>G
ENST00000343455.7:c.5465A>G
ENST00000393063.5:c.5465A>G
ENST00000526495.5:c.5465A>G
ENST00000527414.5:c.5465A>G
ENST00000527416.2:n.58A>G
ENST00000527554.2:n.158A>G
ENST00000541352.5:c.5365-156A>G
ENST00000556045.5:c.2159A>G
NM_001195573.1:c.5365-156A>G
NM_001271282.2:c.5465A>G
NM_001291628.1:c.5465A>G
NM_030621.4:c.5465A>G
NM_177438.2:c.5465A>G
NM_001271282.3:c.5465A>G
NM_001291628.2:c.5465A>G
NM_001395677.1:c.5465A>G
NM_001395678.1:c.5465A>G
NM_001395679.1:c.5465A>G
NM_001395680.1:c.5465A>G
NM_001395682.1:c.5465A>G
NM_001395683.1:c.5465A>G
NM_001395684.1:c.5465A>G
NM_001395685.1:c.5465A>G
NM_001395686.1:c.5183A>G
NM_001395687.1:c.5060A>G
NM_001395688.1:c.5060A>G
NM_001395689.1:c.5060A>G
NM_001395690.1:c.5060A>G
NM_001395691.1:c.4898A>G
NM_001395697.1:c.3782A>G
NR_172715.1:n.5883A>G
NR_172716.1:n.6067A>G
NR_172717.1:n.5977A>G
NR_172718.1:n.5900A>G
NR_172719.1:n.5733A>G
NR_172720.1:n.5936A>G
More

Likely Pathogenic

Met criteria codes 5
PM1_Supporting PM2_Supporting PP1 PP3 PS4_Moderate
Not Met criteria codes 15
BA1 PS2 PS3 PS1 PVS1 PP4 PM4 PM5 BS4 BS3 BS1 BS2 BP7 BP2 BP4

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_177438.3:c.5465A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1822 (p.Asp1822Gly). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate; Ambry). The variant has been reported to segregate with Sertoli Leydig cell tumors, PPB, and lung cysts in 4 meioses from 2 families (PP1; Ambry). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.956) (PP3). This variant resides within the RNase IIIb 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 Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PP1, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 6; VCEP specifications version 1.3.0; 10/22/2024)
Met criteria codes
PM1_Supporting
This variant resides within the RNase IIIb 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 v4.1.0 (PM2_Supporting).
PP1
The variant has been reported to segregate with Sertoli Leydig cell tumors, PPB, and lung cysts in 4 meioses from 2 families (PP1; Ambry).
PP3
In silico tools predict damaging impact of the variant on protein function (REVEL: 0.956) (PP3).
PS4_Moderate
This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate; Ambry).
Not Met criteria codes
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
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PM5
Two different missense variants, c.5465A>T (p.Asp1822Val) and c.5464G>A (p.Asp1822Asn), in the same codon have been reported (ClinVar Variation IDs: 254350, 843033). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
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
BS2
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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