Variant: NM_177438.3(DICER1):c.2523A>G (p.Gln841=)

CA487844850

1676595 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 3d3008a7-77b6-4253-a375-b8db070aaaaf

Approved on: 2025-04-22

Published on: 2025-07-08

HGVS expressions

NM_177438.3:c.2523A>G
NM_177438.3(DICER1):c.2523A>G (p.Gln841=)
NC_000014.9:g.95108007T>C
CM000676.2:g.95108007T>C
NC_000014.8:g.95574344T>C
CM000676.1:g.95574344T>C
NC_000014.7:g.94644097T>C
NG_016311.1:g.54416A>G
ENST00000529720.2:c.2523A>G
ENST00000531162.7:c.2523A>G
ENST00000674628.2:c.2523A>G
ENST00000675540.2:c.2523A>G
ENST00000696733.1:c.2523A>G
ENST00000696734.1:c.2523A>G
ENST00000696736.1:c.2523A>G
ENST00000696737.1:c.2523A>G
ENST00000696738.1:n.411A>G
ENST00000696920.1:n.2786A>G
ENST00000696921.1:n.3629A>G
ENST00000696922.1:n.2932A>G
ENST00000696923.1:c.2523A>G
ENST00000696924.1:c.2523A>G
ENST00000696925.1:n.2932A>G
ENST00000343455.8:c.2523A>G
ENST00000393063.6:c.2523A>G
ENST00000526495.6:c.2523A>G
ENST00000532939.3:c.2523A>G
ENST00000556045.6:c.2523A>G
ENST00000675540.1:c.345A>G
ENST00000675995.1:c.*839A>G
ENST00000343455.7:c.2523A>G
ENST00000393063.5:c.2523A>G
ENST00000526495.5:c.2523A>G
ENST00000527414.5:c.2523A>G
ENST00000541352.5:c.2523A>G
NM_001195573.1:c.2523A>G
NM_001271282.2:c.2523A>G
NM_001291628.1:c.2523A>G
NM_030621.4:c.2523A>G
NM_177438.2:c.2523A>G
NM_001271282.3:c.2523A>G
NM_001291628.2:c.2523A>G
NM_001395677.1:c.2523A>G
NM_001395678.1:c.2523A>G
NM_001395679.1:c.2523A>G
NM_001395680.1:c.2523A>G
NM_001395682.1:c.2523A>G
NM_001395683.1:c.2523A>G
NM_001395684.1:c.2523A>G
NM_001395685.1:c.2523A>G
NM_001395686.1:c.2241A>G
NM_001395687.1:c.2118A>G
NM_001395688.1:c.2118A>G
NM_001395689.1:c.2118A>G
NM_001395690.1:c.2118A>G
NM_001395691.1:c.1956A>G
NM_001395692.1:c.2523A>G
NM_001395693.1:c.2523A>G
NM_001395694.1:c.2523A>G
NM_001395695.1:c.2523A>G
NM_001395696.1:c.2118A>G
NM_001395697.1:c.840A>G
NR_172715.1:n.2941A>G
NR_172716.1:n.2868A>G
NR_172717.1:n.3035A>G
NR_172718.1:n.3035A>G
NR_172719.1:n.2868A>G
NR_172720.1:n.2868A>G

Likely Pathogenic

• Met criteria codes: PS4_Supporting PP4 PP3 PS3 PM2_Supporting

• Not Met criteria codes: BA1 BP7 BP2 BP4 PVS1 BS4 BS3 BS1 BS2 PP1 PS1 PS2 PM1 PM5 PM4

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_177438.3:c.2523A>G (p.Gln841=) variant is a synonymous (silent) variant that is predicted to impact splicing. This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 36922881). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 36922881). This variant has an allele frequency of 6.197e-7 (1/1613606 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMIDs: 36922881, 39484203; Internal lab contributors). The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (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, PP4, PM2_Supporting, PS3, PP3. (Bayesian Points: 8; VCEP specifications version 1.3.0; 4/22/2025)

Met criteria codes

• PS4_Supporting: This variant received a total of 1 phenotype points across 1 unrelated proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 36922881).
• PP4: At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMID: 36922881).
• PP3: The splice site predictor SpliceAI indicates that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3).
• PS3: Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; PMIDs: 36922881, 39484203; Internal lab contributors). Note: Invitae also has damaging RNA sequencing data
• PM2_Supporting: This variant has an allele frequency of 6.197e-7 (1/1613606 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: The NM_177438.3:c.2523A>G (p.Gln841=) variant is a synonymous (silent) variant. However, BP7 was not applied because SpliceAI predicts an impact on splicing, meeting PP3.
• 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
• PVS1: 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
• BS2: 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
• PS1: 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
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 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