Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NR_172720.1:n.2097+213A>G

CA2573334965

2573146 (ClinVar)

Gene: DICER1 (HGNC:23405)

Condition: DICER1-related tumor predisposition (MONDO:0100216)

Inheritance Mode: Autosomal dominant inheritance

UUID: 4f342f03-394b-4d11-a041-8ffb92e11765

Approved on: 2025-08-26

Published on: 2025-09-19

HGVS expressions

NR_172720.1:n.2097+213A>G

NC_000014.9:g.95116240T>C

CM000676.2:g.95116240T>C

NC_000014.8:g.95582577T>C

CM000676.1:g.95582577T>C

NC_000014.7:g.94652330T>C

NG_016311.1:g.46183A>G

ENST00000529720.2:c.1752+213A>G

ENST00000531162.7:c.1752+213A>G

ENST00000674628.2:c.1752+213A>G

ENST00000675540.2:c.1752+213A>G

ENST00000696733.1:c.1752+213A>G

ENST00000696734.1:c.1752+213A>G

ENST00000696736.1:c.1752+213A>G

ENST00000696737.1:c.1752+213A>G

ENST00000696920.1:n.2015+213A>G

ENST00000696921.1:n.2858+213A>G

ENST00000696922.1:n.2161+213A>G

ENST00000696923.1:c.1752+213A>G

ENST00000696924.1:c.1752+213A>G

ENST00000696925.1:n.2161+213A>G

ENST00000696927.1:n.1347+213A>G

ENST00000696928.1:n.1949+213A>G

ENST00000343455.8:c.1752+213A>G

ENST00000393063.6:c.1752+213A>G

ENST00000526495.6:c.1752+213A>G

ENST00000532939.3:c.1752+213A>G

ENST00000556045.6:c.1752+213A>G

ENST00000675995.1:c.*68+213A>G

ENST00000343455.7:c.1752+213A>G

ENST00000393063.5:c.1752+213A>G

ENST00000526495.5:c.1752+213A>G

ENST00000527414.5:c.1752+213A>G

ENST00000532458.1:n.341+213A>G

ENST00000541352.5:c.1752+213A>G

NM_001195573.1:c.1752+213A>G

NM_001271282.2:c.1752+213A>G

NM_001291628.1:c.1752+213A>G

NM_030621.4:c.1752+213A>G

NM_177438.2:c.1752+213A>G

NM_001271282.3:c.1752+213A>G

NM_001291628.2:c.1752+213A>G

NM_177438.3:c.1752+213A>G

NM_001395677.1:c.1752+213A>G

NM_001395678.1:c.1752+213A>G

NM_001395679.1:c.1752+213A>G

NM_001395680.1:c.1752+213A>G

NM_001395682.1:c.1752+213A>G

NM_001395683.1:c.1752+213A>G

NM_001395684.1:c.1752+213A>G

NM_001395685.1:c.1752+213A>G

NM_001395686.1:c.1470+213A>G

NM_001395687.1:c.1347+213A>G

NM_001395688.1:c.1347+213A>G

NM_001395689.1:c.1347+213A>G

NM_001395690.1:c.1347+213A>G

NM_001395691.1:c.1185+213A>G

NM_001395692.1:c.1752+213A>G

NM_001395693.1:c.1752+213A>G

NM_001395694.1:c.1752+213A>G

NM_001395695.1:c.1752+213A>G

NM_001395696.1:c.1347+213A>G

NM_001395697.1:c.69+213A>G

NM_001395698.1:c.1347+213A>G

NR_172715.1:n.2170+213A>G

NR_172716.1:n.2097+213A>G

NR_172717.1:n.2264+213A>G

NR_172718.1:n.2264+213A>G

NR_172719.1:n.2097+213A>G

Likely Pathogenic

PM2_Supporting PS4_Supporting PS3 PP4 PP1 PP3

PM1 BA1 BS3 BS1 BP7 BP2 BP4 PS2

Evidence Links 0

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 1.4.0

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.1752+213A>G variant in DICER1 is an intronic variant located 213 base pairs downstream of exon 10. 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: 37883719). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing (PMID: 37883719), which is highly specific for DICER1 syndrome (PP4, PMID: 34398502). The variant has been reported to segregate with DICER1-spectrum tumors in 3 meioses from 1 family (PP1; PMID: 37883719). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Sequencing of RNA from patients showed an in-frame splicing impact resulting in a premature stop codon and NMD, indicating that this variant impacts protein function (PS3; Invitae, UT Southwestern). The splice site predictors MaxEntScan and SpliceAI indicate 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, PP1, PM2_Supporting, PS3, PP3, (Bayesian Points: 9; VCEP specifications version 1.4.0; 08/26/2025)

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (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; UT Southwestern).

PS3

Sequencing of RNA from patients showed an in-frame splicing impact resulting in a premature stop codon and NMD, indicating that this variant impacts protein function (PS3; Invitae, UT Southwestern). RT-PCR assay from a tumor sample showed a splicing impact leading to a cryptic exon insertion in intron 10 (UT Southwestern). RNA analysis on both proband and father shows a cryptic exon insertion in intron 10, r.1752_1753ins1752+82_1752+212 (131 nucleotides) with an in-frame stop codon. NMD+. Fold change at junction 0.42. (Invitae)

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 syndrome (PP4, PMID: 34398502, UT Southwestern).

PP1

The variant has been reported to segregate with DICER1-spectrum tumors in 3 meioses from 1 family (PP1_Supporting; UT Southwestern).

PP3

SpliceAI Donor Gain: 0.96; MES Native donor 10.57-->10.57, Donor Gain n/a -->8.92 The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3).

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).

BA1