Variant classification summary

NM_177438.3:c.5437G>C

DICER1 · NP_803187.1:p.(Glu1813Gln) · NM_177438.3

GRCh37: chr14:95557630 C>G · GRCh38: chr14:95091293 C>G

Gene: DICER1 Transcript: NM_177438.3

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.(Glu1813Gln)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

PP3_Supporting is met: REVEL score is 0.859, meeting the DICER1 VCEP threshold of ≥ 0.750 for missense variants.

4

PVS1 is not applicable: this is a missense variant and does not fall into the VCEP-defined null-variant buckets (nonsense, frameshift, canonical splice).

5

PS1 is not met: no comparator variant encoding p.Glu1813Gln has been classified as Pathogenic by the DICER1 VCEP.

6

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.

7

PM5 is not applicable per VCEP rule: PM5 cannot be applied in combination with PM1, and PM1_Moderate is met.

8

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).

9

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).

Final determination: 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 yields a total score of 4, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	cspec
PS1	Not met	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).	clinvar cspec
PS2	Not met	No de novo observations with confirmed maternity and paternity were identified for this variant in the reviewed literature or ClinVar submissions.
PS3	Not met	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.	PMID:22187960 spliceai
PS4	Not met	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.	clinvar
PS5	N/A	Not in the ONLY ASSESS list — skipped per instruction.
PM1	Met	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.	cspec PMID:17920623
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	The 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.	cspec
PM6	N/A	The DICER1 VCEP has combined PM6 with PS2 and directs users to apply PS2 instead. PM6 is marked Not Applicable per CSPEC.	cspec
PP1	Not met	No segregation data across affected family members were identified for this variant in the reviewed literature or ClinVar submissions.
PP2	N/A	The 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.	cspec
PP3	Met	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 spliceai cspec
PP4	N/A	The 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.	cspec
PP5	N/A	PP5 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	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	Not met	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.	cspec
BS4	Not met	No family segregation data demonstrating phenotype-positive, genotype-negative relatives were identified for this variant.
BP1	N/A	The DICER1 VCEP marks BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in DICER1.	cspec
BP2	Not met	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.
BP3	N/A	Skipped per instruction — in-frame indels in repetitive region; this is a substitution variant.
BP4	Not met	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.	revel spliceai cspec
BP5	N/A	The 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.	cspec
BP6	N/A	BP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 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.	cspec

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