Variant classification summary

NM_177438.2:c.5125G>C

DICER1 · NP_803187.1:p.(Asp1709His) · NM_177438.2

GRCh37: chr14:95560464 C>G · GRCh38: chr14:95094127 C>G

Gene: DICER1 Transcript: NM_177438.2

Final call

Likely Pathogenic

PS2 moderate PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Asp1709His)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.2:c.5125G>C (p.Asp1709His) alters a metal ion-binding residue in the RNase IIIb catalytic domain of DICER1, meeting PM1 at moderate strength per the ClinGen DICER1 VCEP.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength (VCEP threshold: AF <0.000005).

3

REVEL score of 0.988 exceeds the VCEP PP3 threshold of ≥0.750, with no predicted splicing impact (SpliceAI max delta = 0.00), meeting PP3 at supporting strength.

4

A confirmed de novo occurrence was reported in an infant with pituitary blastoma, bilateral lung cysts, and bilateral renal cystic masses (de Kock et al. 2014), meeting PS2 at moderate strength (1 de novo point).

5

Per the DICER1 VCEP Tavtigian point-based system: PM1_Moderate (2) + PM2_Supporting (1) + PP3_Supporting (1) + PS2_Moderate (2) = 6 points, which falls in the Likely Pathogenic range (≥6, ≤9).

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 6, which maps to Likely Pathogenic 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_177438.2:c.5125G>C is a missense variant (p.Asp1709His). The DICER1 VCEP PVS1 rules apply only to nonsense, frameshift, and canonical splice site variants. This missense variant does not fall into any PVS1 bucket per the VCEP PVS1 decision tree.	vcep_pvs1_decisiontree pvs1_variant_assessment
PS1	Not met	PS1 requires a different nucleotide change producing the same amino acid change (p.Asp1709His) that is classified as pathogenic by the ClinGen DICER1 VCEP. Asp1709 (GAC) can only become His via a single nucleotide change (G>C at position 5125). No alternative nucleotide variant producing the same Asp1709His change exists, and no VCEP-classified pathogenic comparator was identified.
PS2	Met	A confirmed de novo occurrence of NM_177438.2:c.5125G>C (p.Asp1709His) was reported in a child (case 12) with pituitary blastoma, bilateral lung cysts, and bilateral renal cystic masses (de Kock et al. 2014, PMID:24839956). Per DICER1 VCEP PS2 rules, one confirmed de novo observation yields 1 de novo point, meeting the moderate threshold (≥1 but <2 points).	PMID:24839956
PS3	Not met	The DICER1 VCEP PS3 rules require variant-specific RNA splicing assay or in vitro cleavage assay data. No variant-specific functional assay (RNA splicing or pre-miRNA cleavage) has been performed for c.5125G>C. The general knowledge that Asp1709 is a metal ion-binding residue in the RNase IIIb domain is captured by PM1; it does not constitute variant-specific functional evidence for PS3. SpliceAI predicts no splicing impact (max delta = 0.00), so no RNA splicing assay is indicated.	spliceai
PS4	Not met	The DICER1 VCEP PS4 rule requires phenotype points from unrelated probands with DICER1-specific phenotypes. While a single proband (case 12) has been reported with this variant and pituitary blastoma, the required phenotype point tabulation and scoring against the VCEP phenotype table cannot be completed from the available data without additional proband summaries.	PMID:24839956
PS5	N/A	PS5 is not a criterion defined by the DICER1 VCEP framework or the standard ACMG/AMP 2015 criteria. The counterpart PP5 is explicitly not applicable for this VCEP.
PM1	Met	p.Asp1709 is one of seven metal ion-binding residues (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) explicitly defined by the DICER1 VCEP as meeting PM1 at moderate strength. The variant p.Asp1709His alters a critical metal ion-binding residue in the RNase IIIb catalytic domain.	PMID:24839956
PM2	Met	NM_177438.2:c.5125G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. This satisfies the DICER1 VCEP PM2 rule: allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	The DICER1 VCEP PM5 rule explicitly states it cannot be applied in combination with PM1 or PS1. Since PM1_Moderate is met at this residue (p.D1709 is a metal ion-binding hotspot), PM5 is precluded by VCEP rule.
PM6	N/A	The DICER1 VCEP has opted to drop PM6 and exclusively use PS2 for de novo evidence.
PP1	Not met	No co-segregation data are available for this variant. The DICER1 VCEP requires 3-4 meioses for supporting, 5-6 for moderate, and ≥7 for strong with affected family members having high/moderate-specificity phenotypes.
PP2	N/A	The DICER1 VCEP recommends PP2 not be used for DICER1 due to the presence of benign/likely benign missense variants in ClinVar despite the gene meeting the missense constraint z-score cutoff.
PP3	Met	REVEL score is 0.988, which is ≥0.750, meeting the DICER1 VCEP PP3 threshold for missense variants. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with pathogenicity being mediated through the amino acid change rather than altered splicing.	revel spliceai
PP4	N/A	The DICER1 VCEP explicitly states PP4 is NOT applicable if the germline variant is a missense variant in one of the seven RNase IIIb hotspot codons. p.Asp1709 is one of those seven codons (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813).
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP explicitly marks PP5 as not applicable.
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. The DICER1 VCEP BA1 threshold requires allele frequency >0.003 (0.3%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. The DICER1 VCEP BS1 threshold requires allele frequency >0.0003 (0.03%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present.	gnomad_v2 gnomad_v4
BS2	Not met	No observations of homozygosity and no data on tumor-free adult females through age 50 are available for this variant.
BS3	Not met	The DICER1 VCEP BS3 requires functional evidence of no splicing impact or intact pre-miRNA cleavage. No such functional data exist for this variant. The VCEP BS3_Strong is for intronic/synonymous variants with normal RNA splicing; BS3_Supporting requires in vitro cleavage assay showing normal function. Neither applies to this missense variant with no functional assay data.
BS4	Not met	No segregation data demonstrating lack of segregation in affected family members are available. The DICER1 VCEP requires phenotype-positive, genotype-negative 1st/2nd/3rd degree relatives of the proband.
BP1	N/A	The DICER1 VCEP states BP1 is not applicable because truncating variants account for only a portion of disease-causing variants in DICER1; missense variants are a common mechanism of disease.
BP2	Not met	No observations of this variant in trans with a pathogenic/likely pathogenic DICER1 variant or in cis with multiple P/LP variants are available.
BP4	Not met	The DICER1 VCEP BP4 rule for missense variants requires REVEL <0.500 and agreement in splicing predictors of no splicing effect. REVEL score is 0.988, which far exceeds the BP4 threshold. This variant is computationally predicted to be damaging, not benign.	revel spliceai
BP5	N/A	The DICER1 VCEP states BP5 is not applicable due to the broad spectrum of DICER1-related neoplasms and lack of evidence of other high-penetrance germline variants that could account for such phenotypes.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP explicitly marks BP6 as not applicable.
BP7	N/A	NM_177438.2:c.5125G>C is a missense variant, not a silent/synonymous or intronic variant. BP7 applies only to silent variants or intronic variants at or beyond +7 to -21 positions.

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