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

CA487844850

1676595 (ClinVar)

Gene: DICER1

Condition: dicer1 syndrome

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2023-02-28

Published on: 2023-03-01

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
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:n.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

Uncertain Significance

• Met criteria codes: PM2_Supporting PS4_Supporting PP4 PP3

• Not Met criteria codes: PM4 BA1 BS3 BS1 BP7 BP3 BP4 PS3 PVS1

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

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.3:c.2523A>G is a synonymous variant (p.Gln841=) that is predicted to impact splicing. The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). 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 syndrome (PP4, PPB Registry, c.5125G>A (p.D1709N)). This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Children's Minnesota). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 and miRNA-Processing Gene VCEP: PS4_Supporting, PM2_Supporting, PP3, PP4 (Bayesian Points: 4, VCEP specifications version 1.1.0; 2/28/2023).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting).
• 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; Children's Minnesota).
• PP4: At least one patient with this variant displayed a somatic hotspot variant in the tumor, c.5125G>A (p.D1709N), which is highly specific for PPB (PP4, PPB Registry).
• PP3: The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3).

Not Met criteria codes

• PM4: 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
• 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: 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
• PS3: External RNA data was presented to and considered by the VCEP. However, it was considered to be borderline, so PS3_Moderate was not applied.
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline