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.1 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 < 0.000005.2 PP3_Supporting is met: REVEL score is 0.859, meeting the DICER1 VCEP threshold of ≥ 0.750 for missense variants.3 PVS1 is not applicable: this is a missense variant and does not fall into the VCEP-defined null-variant buckets (nonsense, frameshift, canonical splice).4 PS1 is not met: no comparator variant encoding p.Glu1813Gln has been classified as Pathogenic by the DICER1 VCEP.5 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.6 PM5 is not applicable per VCEP rule: PM5 cannot be applied in combination with PM1, and PM1_Moderate is met.7 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).8 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).9
DICER1
Final classification
VUS
PM1PM2PP3
DICER1
c.5437G>C
p.Glu1813Gln
This variant
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.
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.
Classification rationale
PM1PM2PP3
VUS
DICER1 c.5437G>C
PM1 + PM2 + PP3
→
VUS
Gene diagram
· NM_177438.3 · variants mapped to exon structure
DICER1
NM_177438.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
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.
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.
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)and gnomAD-Canada (0 alleles).
✓
PP3
supporting
Pathogenic
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.
REVEL = 0.859 (≥0.750 threshold met). SpliceAI max delta = 0.00.
Assessed · not applied
· 12 not met · 0 not assessed
Pathogenic
PS1
No comparator variant encoding the same amino acid change (p.Glu1813Gln) has been classified as Pathogenic by the ClinGen DICER1 VCEP.
PS2
No de novo observations with confirmed maternity and paternity were identified for this variant in the reviewed literature or ClinVar submissions.
PS3
No variant-specific functional data are available for p.Glu1813Gln.
PS4
Insufficient proband phenotype data are available to tally phenotype points under the DICER1 VCEP PS4 rules.
PP1
No segregation data across affected family members were identified for this variant in the reviewed literature or ClinVar submissions.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles).
BS1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles).
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.
BS3
No variant-specific functional studies demonstrating normal DICER1 function are available.
BS4
No family segregation data demonstrating phenotype-positive, genotype-negative relatives were identified for this variant.
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.
BP4
REVEL score is 0.859, which does not meet the DICER1 VCEP BP4_Supporting threshold of REVEL < 0.500 for missense variants.
N/A · 11
PVS1 · PM5 · PM6 · PP2 · PP4 · PP5 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58617855, n = 21 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
17920623 ↗
Homodimeric structure and double-stranded RNA cleavage activity of the C-terminal RNase III domain of human dicer.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
21205968 ↗
DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors.
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
26475046 ↗
High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome.
CLINVAR
27459524 ↗
Deep Sequencing Reveals Spatially Distributed Distinct Hot Spot Mutations in DICER1-Related Multinodular Goiter.
CLINVAR
29037807 ↗
DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry.
CLINVAR