Variant: NM_177438.2(DICER1):c.4748T>G (p.Leu1583Arg)

CA212568

4468 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: f699f55d-24ea-4c9b-882c-9ad1dc4b7531

Approved on: 2024-10-22

Published on: 2024-11-13

HGVS expressions

NM_177438.2:c.4748T>G
NM_177438.2(DICER1):c.4748T>G (p.Leu1583Arg)
NC_000014.9:g.95096172A>C
CM000676.2:g.95096172A>C
NC_000014.8:g.95562509A>C
CM000676.1:g.95562509A>C
NC_000014.7:g.94632262A>C
NG_016311.1:g.66251T>G
ENST00000529720.2:c.4748T>G
ENST00000531162.7:c.4748T>G
ENST00000674628.2:c.4748T>G
ENST00000675540.2:c.*1398T>G
ENST00000696733.1:c.4748T>G
ENST00000696734.1:c.4748T>G
ENST00000696735.1:n.1735T>G
ENST00000696736.1:c.4748T>G
ENST00000696737.1:c.4748T>G
ENST00000696920.1:n.5011T>G
ENST00000696921.1:n.5854T>G
ENST00000696922.1:n.5157T>G
ENST00000696923.1:c.4748T>G
ENST00000696924.1:c.4748T>G
ENST00000696925.1:n.5157T>G
ENST00000343455.8:c.4748T>G
ENST00000393063.6:c.4748T>G
ENST00000526495.6:c.4748T>G
ENST00000532939.3:c.4748T>G
ENST00000556045.6:c.4748T>G
ENST00000675540.1:c.2493T>G
ENST00000675995.1:c.*3064T>G
ENST00000343455.7:c.4748T>G
ENST00000393063.5:c.4748T>G
ENST00000526495.5:c.4748T>G
ENST00000527414.5:c.4748T>G
ENST00000532939.2:c.783T>G
ENST00000541352.5:c.4748T>G
ENST00000556045.5:c.1442T>G
NM_001195573.1:c.4748T>G
NM_001271282.2:c.4748T>G
NM_001291628.1:c.4748T>G
NM_030621.4:c.4748T>G
NM_001271282.3:c.4748T>G
NM_001291628.2:c.4748T>G
NM_177438.3:c.4748T>G
NM_001395677.1:c.4748T>G
NM_001395678.1:c.4748T>G
NM_001395679.1:c.4748T>G
NM_001395680.1:c.4748T>G
NM_001395682.1:c.4748T>G
NM_001395683.1:c.4748T>G
NM_001395684.1:c.4748T>G
NM_001395685.1:c.4748T>G
NM_001395686.1:c.4466T>G
NM_001395687.1:c.4343T>G
NM_001395688.1:c.4343T>G
NM_001395689.1:c.4343T>G
NM_001395690.1:c.4343T>G
NM_001395691.1:c.4181T>G
NM_001395692.1:c.4748T>G
NM_001395693.1:c.4748T>G
NM_001395694.1:c.4748T>G
NM_001395695.1:c.4748T>G
NM_001395696.1:c.4343T>G
NM_001395697.1:c.3065T>G
NR_172715.1:n.5166T>G
NR_172716.1:n.5350T>G
NR_172717.1:n.5260T>G
NR_172718.1:n.5183T>G
NR_172719.1:n.5016T>G
NR_172720.1:n.5093T>G

Likely Pathogenic

• Met criteria codes: PS4_Supporting PP3 PM2_Supporting PP1_Moderate PS3_Supporting

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP2 BP4 PS2 PS1 PP4 PM1 PM5 BA1

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

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

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.2:c.4748T>G variant in DICER1 is a missense variant predicted to cause substitution of leucine by arginine at amino acid 1583 (p.Leu1583Arg). This variant received a total of 1 phenotype point(s) across 1 family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 19556464). The variant has been reported to segregate with PPB and lung cysts in 3 affected family members (5 meioses) from 1 family (PP1_Moderate; PMID: 19556464). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Leu1583Arg 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 (PS3_Supporting; Wu et al., McGill, 2018). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.894) (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_Supporting, PP1_Moderate, PM2_Supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1.3.0; 10/22/2024)

Met criteria codes

• PS4_Supporting: This variant received a total of 1 phenotype point(s) across 1 family meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 19556464). Reported as 4930T>G (L1573R) in 3 family members with DICER1-related phenotypes (PMID: 19556464).
• PP3: In silico tools predict damaging impact of the variant on protein function (REVEL: 0.894) (PP3).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PP1_Moderate: The variant has been reported to segregate with PPB and lung cysts in 3 affected family members (5 meioses) from 1 family (PP1_Moderate; PMID: 19556464).
• PS3_Supporting: In vitro cleavage assay carried out using immunopurified DICER1 variant Leu1583Arg 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(PS3_Supporting; Wu et al., McGill, 2018).

Not Met criteria codes

• 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
• 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
• 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
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
• PM5: Three different missense variants, c.4748T>C (p.Leu1583Pro), c.4747C>G (p.Leu1583Val), c.4747C>T (p.Leu1583Phe), in the same codon have been reported (ClinVar Variation ID: 2674821, 1712560, 659266). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met). Grantham Leu>Arg=102 Leu>Pro=98 Leu>Val=32 Leu>Phe=22
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline