About DICER1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DICER1 c.5437G>C, p.(Glu1813Gln)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen DICER1 VCEP v1.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
The variant results in p.Glu1813Gln, affecting codon p.E1813, which is one of the seven metal ion-binding residues in the RNase IIIb domain explicitly listed in the DICER1 VCEP PM1 moderate rule (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813). Crystal structure data (PMID:17920623) confirm E1813 directly coordinates the catalytic Mg-1 ion.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with zero alleles observed across all populations. This satisfies the DICER1 VCEP PM2_Supporting threshold of allele frequency < 0.000005 with no more than one allele in any subpopulation.
PP3Supporting
PP3 · supporting
REVEL score is 0.859, which meets the DICER1 VCEP PP3_Supporting threshold of ≥ 0.750 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), so the splicing arm of PP3 is not applicable.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4.0 v1.4.0 point-based framework: PM1 moderate (+2) + PM2 supporting (+1) + PP3 supporting (+1) = 4 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
21 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58617855, n = 21 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4.0, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1_Moderate is met: p.Glu1813Gln affects codon p.E1813, a metal ion-binding residue in the RNase IIIb domain explicitly listed in the DICER1 VCEP PM1 moderate rule. Crystal structure data confirm E1813 coordinates the catalytic Mg-1 ion.
PM2_Supporting is met: NM_177438.3:c.5437G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles across all populations), satisfying the VCEP threshold of AF < 0.000005.
PP3_Supporting is met: REVEL score is 0.859, meeting the DICER1 VCEP threshold of ≥ 0.750 for missense variants.
PVS1 is not applicable: this is a missense variant and does not fall into the VCEP-defined null-variant buckets (nonsense, frameshift, canonical splice).
PS1 is not met: no comparator variant encoding p.Glu1813Gln has been classified as Pathogenic by the DICER1 VCEP.
PS3 is not met: no variant-specific functional assay has been performed for p.Glu1813Gln. The cleavage assay in PMID:22187960 tested D1709N, D1709E, and E1705K but not E1813Q.
PM5 is not applicable per VCEP rule: PM5 cannot be applied in combination with PM1, and PM1_Moderate is met.
PP4 is not applicable per VCEP rule: the germline variant itself is a missense in one of the seven RNase IIIb hotspot codons (p.E1813).
With PM1_Moderate (+2), PM2_Supporting (+1), and PP3_Supporting (+1), the total Tavtigian point score is +4, which falls in the DICER1 VCEP Uncertain Significance range (-1 to +5).
No criteria match.
Met · 3
PM1 ModerateThe variant results in p.Glu1813Gln, affecting codon p.E1813, which is one of the seven metal ion-binding residues in the RNase IIIb domain explicitly listed in the DICER1 VCEP PM1 moderate rule (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813). Crystal structure data (PMID:17920623) confirm E1813 directly coordinates the catalytic Mg-1 ion. Details ▾Hide ▴
Evidence considered
- p.E1813 is a VCEP-listed metal ion-binding hotspot residue. Crystal structure confirms E1813 coordinates Mg-1 at the RNase IIIb active site. Statistically significant hotspot in evidence_brief.
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with zero alleles observed across all populations. This satisfies the DICER1 VCEP PM2_Supporting threshold of allele frequency < 0.000005 with no more than one allele in any subpopulation. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada (0 alleles).
Sources
PP3 SupportingREVEL score is 0.859, which meets the DICER1 VCEP PP3_Supporting threshold of ≥ 0.750 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), so the splicing arm of PP3 is not applicable. Details ▾Hide ▴
Evidence considered
- REVEL = 0.859 (≥0.750 threshold met). SpliceAI max delta = 0.00.
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No comparator variant encoding the same amino acid change (p.Glu1813Gln) has been classified as Pathogenic by the ClinGen DICER1 VCEP. The variant under evaluation is the only known instance of E1813Q; ClinVar currently classifies it as Uncertain significance (VCV000933089). Details ▾Hide ▴
PS2 No de novo observations with confirmed maternity and paternity were identified for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo data available for PS2 point tally.
Still missing
- No de novo proband data identified.
PS3 No variant-specific functional data are available for p.Glu1813Gln. The in vitro cleavage assay in Heravi-Moussavi et al. (2012, PMID:22187960) tested D1709N, D1709E, and E1705K, but not E1813Q. SpliceAI predicts no splicing impact (max delta = 0.00), so the PS3 splicing arm does not apply. No in vitro cleavage assay demonstrating reduced 5p or 3p miRNA production has been performed for this specific variant. Details ▾Hide ▴
Evidence considered
- PMID:22187960 functional assays did not include E1813Q. SpliceAI max delta 0.00
- no splicing impact predicted.
Still missing
- No variant-specific RNA assay or in vitro cleavage assay for E1813Q.
Sources
PS4 Insufficient proband phenotype data are available to tally phenotype points under the DICER1 VCEP PS4 rules. The ClinVar submission from Foulkes Cancer Genetics LDI classifies this variant as Pathogenic, but no structured phenotype point tally from unrelated probands with high- or moderate-specificity DICER1 phenotypes was identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- ClinVar SCV001372124 classifies as Pathogenic (single submitter)
- but insufficient phenotype point data for VCEP PS4 tally.
Still missing
- No structured proband phenotype point tally available for PS4 assessment.
Sources
PP1 No segregation data across affected family members were identified for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No co-segregation data available for PP1 meiosis tally.
Still missing
- No segregation data identified.
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles). Does not meet the DICER1 VCEP BA1 threshold of frequency > 0.003 (0.3%) in any subpopulation with > 2,000 alleles and ≥ 5 alleles present. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD populations
- AF = 0 does not exceed BA1 threshold of 0.003.
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles). Does not meet the DICER1 VCEP BS1 threshold of frequency > 0.0003 (0.03%) in any subpopulation with > 2,000 alleles and ≥ 5 alleles present. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD populations
- AF = 0 does not exceed BS1 threshold of 0.0003.
Sources
BS2 No observations of homozygosity in healthy individuals and no cohort data for 10+ or 40+ tumor-free unrelated females through age 50 were identified for this variant. Details ▾Hide ▴
Evidence considered
- No BS2-eligible observations identified.
Still missing
- No homozygosity or healthy-female cohort data available.
BS3 No variant-specific functional studies demonstrating normal DICER1 function are available. The BS3_Strong rule (no splicing impact via RNA assay) applies only to intronic or synonymous variants; this is a missense variant. The BS3_Supporting rule requires an in vitro cleavage assay demonstrating the variant produces both 5p and 3p miRNAs — no such assay has been performed for p.Glu1813Gln. Details ▾Hide ▴
Evidence considered
- No functional data showing normal DICER1 function for E1813Q. BS3_Strong restricted to intronic/synonymous variants per VCEP.
Still missing
- No variant-specific cleavage assay demonstrating normal function.
Sources
BS4 No family segregation data demonstrating phenotype-positive, genotype-negative relatives were identified for this variant. Details ▾Hide ▴
Evidence considered
- No BS4-eligible segregation data identified.
Still missing
- No family co-segregation data available.
BP2 No observations of this variant in trans with a P/LP DICER1 variant or in cis/phase unknown with multiple different P/LP DICER1 variants were identified. Details ▾Hide ▴
Evidence considered
- No BP2-eligible observations identified.
Still missing
- No trans or cis observations with P/LP DICER1 variants.
BP4 REVEL score is 0.859, which does not meet the DICER1 VCEP BP4_Supporting threshold of REVEL < 0.500 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), but BP4 requires BOTH REVEL < 0.500 AND agreement in splicing predictors; the REVEL condition is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.859 does not satisfy BP4 threshold of <0.500. SpliceAI max delta = 0.00.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_177438.3:c.5437G>C is a missense variant (p.Glu1813Gln) and does not fall into the DICER1 VCEP PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice site variants. The DICER1 VCEP PVS1 decision tree applies only to these variant classes. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant. Does not meet any PVS1 entry criteria per VCEP v1.4.0.
Sources
PM5 N/AThe DICER1 VCEP PM5 rule states: 'This rule cannot be applied in combination with PM1 or PS1.' Since PM1_Moderate is met for this variant (p.E1813 is a metal ion-binding residue), PM5 is excluded per VCEP rule. Details ▾Hide ▴
PM6 VCEPThe DICER1 VCEP has combined PM6 with PS2 and directs users to apply PS2 instead. PM6 is marked Not Applicable per CSPEC. Details ▾Hide ▴
PP2 VCEPThe DICER1 VCEP recommends PP2 not be used. Although DICER1 meets the missense constraint z-score threshold (4.23 on gnomAD), the VCEP notes that various missense variants throughout the gene are clinically interpreted as benign or likely benign in ClinVar. Details ▾Hide ▴
PP4 N/AThe DICER1 VCEP PP4 rule states: 'PP4 is NOT applicable if the germline variant is a missense variant in one of the seven RNase IIIb hotspot codons (see PM1).' The variant under evaluation is p.Glu1813Gln, which affects codon p.E1813 — one of the seven hotspot codons. PP4 is therefore excluded. Details ▾Hide ▴
Evidence considered
- Germline variant is in a hotspot codon (p.E1813). PP4 not applicable per VCEP exclusion rule.
Sources
PP5 VCEPPP5 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP1 VCEPThe DICER1 VCEP marks BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in DICER1. Details ▾Hide ▴
BP3 VCEPSkipped per instruction — in-frame indels in repetitive region; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPThe DICER1 VCEP marks BP5 as Not Applicable: given the broad spectrum of DICER1-related neoplasms and lack of evidence for other high-penetrance germline variants accounting for such phenotypes, this rule should not be used at this time. Details ▾Hide ▴
BP6 VCEPBP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to silent variants, intronic variants at or beyond +7 to -21 positions, or other intronic/non-coding variants. This is a missense variant (p.Glu1813Gln) and does not fall into any BP7-eligible category. Additionally, BP7 requires that BP4 be met — BP4 is not met for this variant. Details ▾Hide ▴
Evidence considered
- Missense variant not eligible for BP7. BP4 not met (REVEL 0.859 > 0.500).
Sources
PS5 N/ANot in the ONLY ASSESS list — skipped per instruction. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- DICER1
- Transcript
- NM_177438.3
- Coding (HGVS c.)
- NM_177438.3:c.5437G>C
- Protein (HGVS p.)
- NP_803187.1:p.(Glu1813Gln)
- GRCh38
- chr14:95091293 C>G
- GRCh37
- chr14:95557630 C>G
- ClinVar
- 933089
- COSMIC
- COSV58617855
Gene diagram
Every interpreted variant in DICER1, mapped onto the exon structure of NM_177438.3. Select a row to find it on the plot.
DICER1NM_177438.3
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.859
- BayesDel
- 0.371
How the predictions were used
PP3 SupportingREVEL score is 0.859, which meets the DICER1 VCEP PP3_Supporting threshold of ≥ 0.750 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), so the splicing arm of PP3 is not applicable. Details ▾Hide ▴
Evidence considered
- REVEL = 0.859 (≥0.750 threshold met). SpliceAI max delta = 0.00.
Sources
BP4 REVEL score is 0.859, which does not meet the DICER1 VCEP BP4_Supporting threshold of REVEL < 0.500 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), but BP4 requires BOTH REVEL < 0.500 AND agreement in splicing predictors; the REVEL condition is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.859 does not satisfy BP4 threshold of <0.500. SpliceAI max delta = 0.00.
Sources
BP7 N/ABP7 applies to silent variants, intronic variants at or beyond +7 to -21 positions, or other intronic/non-coding variants. This is a missense variant (p.Glu1813Gln) and does not fall into any BP7-eligible category. Additionally, BP7 requires that BP4 be met — BP4 is not met for this variant. Details ▾Hide ▴
Evidence considered
- Missense variant not eligible for BP7. BP4 not met (REVEL 0.859 > 0.500).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.859. BayesDel score = 0.370717.
8 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 17920623 ↗Homodimeric structure and double-stranded RNA cleavage activity of the C-terminal RNase III domain of human dicer.Reports the crystal structure of the human DICER1 RNase IIIb domain at 2.0 Å resolution. Demonstrates that E1813 directly coordinates the Mg-1 ion at the catalytic active site, along with E1705 and D1810. Provides structural evidence for the functional importance of the metal ion-binding residues.→ PM1 Does not name this variant
Source detail
Mg-1 is coordinated directly by the carboxylate oxygen atoms of E1705, D1810, and E1813 and by three water molecules
Location Results, Active site section; Figure 5b
Context X-ray crystallography of purified recombinant Hs-Dicer RNase IIIb domain
Other recorded publications
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PMID 21205968 ↗DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors.Rio Frio T et al. · 2011Reports germline DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. NM_177438.3:c.5437G>C was not identified in this paper.Does not name this variant
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PMID 22187960 ↗Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.Heravi-Moussavi A et al. · 2012Identifies c.5437G>C (p.Glu1813Gln) as a somatic hotspot mutation in 2 of 43 Sertoli-Leydig cell tumors. In vitro cleavage assays tested D1709N, D1709E, and E1705K — all showed reduced RNase IIIb activity with retained RNase IIIa activity — but E1813Q was not functionally assessed.Names this variant
Quoted passage
c.5437G→C — 2 — p.Glu1813Gln (E1813Q)
Table 1 (Sertoli-Leydig cell tumor mutations); Results, Functional Characterization section
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PMID 24136150 ↗DICER1 hotspot mutations in non-epithelial gonadal tumours.Witkowski L et al. · 2013Screened DICER1 RNase IIIa and IIIb domains in 154 non-epithelial gonadal tumours. NM_177438.3:c.5437G>C was not identified in this paper.Does not name this variant
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PMID 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.ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a methodological guideline paper that does not discuss any specific DICER1 variants.Does not name this variant
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PMID 26475046 ↗High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome.de Kock L et al. · 2016Identifies c.5437G>C (p.Glu1813Q) as a mosaic DICER1 mutation in Patient 2, detected in 6 tumors and at low level (0.25%) in saliva DNA. Patient had multiple DICER1 syndrome tumors including SLCT. Second somatic truncating mutations and LOH were also identified in tumors.Names this variant
Quoted passage
patient 2: c.5437G>C [p.E1813Q], n=6
Results, paragraph 2; Table 2
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PMID 27459524 ↗Deep Sequencing Reveals Spatially Distributed Distinct Hot Spot Mutations in DICER1-Related Multinodular Goiter.de Kock L et al. · 2016Identifies c.5437G>C (p.Glu1813Gln) as a somatic RNase IIIb hotspot mutation in MNG nodules from DICER1 germline mutation carriers (cases 2, 3, and 7). Multiple spatially distinct hotspot mutations coexist within individual MNGs, consistent with clonally independent somatic events.Names this variant
Quoted passage
c.5437G>C (p.Glu1813Gln)
Table 1; Figures 1-2; Results section
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PMID 29037807 ↗DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry.Describes clinical and genetic findings from 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry. NM_177438.3:c.5437G>C was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243094
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/933089/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-95557630-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-95091293-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-95091293-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_177438.3%3Ac.5437…
- OncoKB ↗www.oncokb.org/gene/DICER1/E1813Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=188088415
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 933089)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.859. BayesDel score = 0.370717.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58617855, n = 21 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.