DICER1 encodes an enzyme that processes RNA into small silencing RNAs and microRNAs, which regulate gene expression after transcription. Germline mutations in DICER1 cause DICER1-related disorders, a familial tumor susceptibility syndrome that increases the risk of pleuropulmonary blastoma, cystic nephroma, rhabdomyosarcoma, multinodular goiter, and ovarian Sertoli-Leydig cell tumors. DICER1 acts as a tumor suppressor, and loss or reduced activity of the protein is linked to cancer development and poorer outcomes in several cancer types, including lung, breast, and ovarian cancers.
This variant
DICER1 is a tumor suppressor whose germline mutations predispose to pleuropulmonary blastoma, cystic nephroma, and other DICER1-related tumors. This missense change (p.Ile846Val) is a VUS: it sits outside the RNase IIIb mutational hotspot and carries only benign-predictive evidence (BP4), with no functional, segregation, or de novo data and a population frequency above rarity thresholds, so it neither confirms nor excludes DICER1-related disease risk.
Transcript
NM_177438.2
HGVS · transcript:coding
NM_177438.2:c.2536A>G
GRCh38
chr14:95107994 T>C
GRCh37
chr14:95574331 T>C
BasisVUS: under the DICER1 VCEP v1.4 point framework only BP4 Supporting (-1 pt) was met; the total of -1 falls in Rule 3 (-1 to +5), giving Uncertain Significance.▾
VUS: under the DICER1 VCEP v1.4 point framework only BP4 Supporting (-1 pt) was met; the total of -1 falls in Rule 3 (-1 to +5), giving Uncertain Significance.
Classification rationale
BP4VUS
DICER1 c.2536A>Gmissense · exon 16
BP4 (Supporting): REVEL 0.191 is below the <0.500 threshold and SpliceAI predicts no splice impact (max delta 0.029). VUS: with only BP4 Supporting applied (-1 pt), the DICER1 VCEP v1.4 total of -1 falls in Rule 3 (-1 to +5), yielding Uncertain Significance.
BP4→VUS
Gene diagram
· NM_177438.2 · variants mapped to exon structure
DICER1NM_177438.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in DICER1—click a row to locate it on the plot · use the link column to open its page
Variant ↕
Protein
Location
Classification
Link
Applied criteria · 1 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
BP4supportingBenign
Met (Supporting): REVEL 0.191 is below the <0.500 threshold and SpliceAI predicts no splice impact (max delta 0.029).
DICER1 VCEP CSpec v1.4 BP4 rule: 'For missense variants, REVEL score < 0.500 and agreement in splicing predictors that no splicing effects are predicted.'Local REVEL v1.3 lookup: score = 0.191 for NM_177438.2:c.2536A>G, below the 0.500 benign-supporting threshold specified by the VCEP.SpliceAI Lookup: max delta score = 0.029 (DS_AG=0.002, DS_AL=0.029, DS_DG=0.0, DS_DL=0.008), indicating no predicted splicing impact, consistent with the 'no splicing effects predicted' component of the VCEP BP4 rule.
This variant is present in gnomAD v4.1 (AF= 3.09898e-05; MAF= 0.00310%, 50/1613432 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.99967e-05; MAF= 0.00500%, 3/60004 alleles, homozygotes = 0); grpmax FAF= 2.989e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98159e-05; MAF= 0.00398%, 10/251156 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.67253e-05; MAF= 0.00867%, 3/34592 alleles, homozygotes = 0); grpmax FAF= 2.858e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0031%
· 50 / 1,613,432
0 hom · FAF 0.003%
Admixed American
3 / 60,004
0.005%
European (non-Finnish)
46 / 1,179,484
0.0039%
Remaining individuals
1 / 62,462
0.0016%
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.004%
· 10 / 251,156
0 hom · FAF 0.0029%
Admixed American
3 / 34,592
0.0087%
European (non-Finnish)
7 / 113,534
0.0062%
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 477106)
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DICER1, an endoribonuclease, is altered in various cancer types.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100601996, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.CLINVAR
25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.CLINVAR
28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.CLINVAR
38084291 ↗Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation.CLINVAR
