Variant classification summary

NM_177438.2:c.1282G>C

DICER1 · NP_803187.1:p.(Glu428Gln) · NM_177438.2

GRCh37: chr14:95590627 C>G · GRCh38: chr14:95124290 C>G

Gene: DICER1 Transcript: NM_177438.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Glu428Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.2:c.1282G>C (p.Glu428Gln) is a missense variant in exon 8 of DICER1, located in the N-terminal DExD helicase domain, outside the RNase IIIb domain and metal ion-binding hotspot residues.

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the DICER1 VCEP PM2_Supporting criterion (AF < 0.000005).

3

Computational evidence suggests a benign effect: REVEL score is 0.186 (< 0.500), BayesDel score is -0.262, and SpliceAI predicts no splicing impact (max delta = 0.00), meeting the DICER1 VCEP BP4_Supporting criterion.

4

The variant has been observed once in somatic cancers (COSMIC COSV100602630) but has not been reported in ClinVar or the germline literature.

5

No functional data, de novo observations, family segregation data, or tumor sequencing data are available to assess PS3, PS2, PP1, or PP4.

6

Under the DICER1 VCEP v1.4 Tavtigian point-based system: PM2_Supporting (+1) + BP4_Supporting (-1) = 0 points, classifying this variant as a Variant of Uncertain Significance.

Final determination: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.4 v1.4 point-based framework yields a total score of 0, 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	PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_177438.2:c.1282G>C is a missense variant (p.Glu428Gln) and is outside the scope of the DICER1 VCEP PVS1 rules.	cspec
PS1	Not met	PS1 requires a different nucleotide change resulting in the same amino acid substitution (p.Glu428Gln) classified as pathogenic by the ClinGen DICER1 VCEP. The variant is absent from ClinVar, and no pathogenic variant at p.Glu428 has been identified.	clinvar cspec
PS2	Not assessed	No de novo data are available for this variant. No literature reports, ClinVar submissions, or other sources document de novo occurrence of NM_177438.2:c.1282G>C.
PS3	Not met	No functional data exist for NM_177438.2:c.1282G>C. SpliceAI predicts no splicing impact (max delta = 0.00), and no RNA assay or in vitro cleavage assay data have been reported. The variant is absent from the literature.	spliceai oncokb
PS4	Not assessed	No clinical phenotype data from unrelated probands are available for this variant. The variant is absent from ClinVar and has not been reported in any published case series or cohorts.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen DICER1 VCEP v1.4 criteria set.	cspec
PM1	Not met	The DICER1 VCEP defines PM1 for missense variants at metal ion-binding residues (p.S1344, E1705, D1709, D1713, G1809, D1810, E1813; moderate) or within the RNase IIIb domain (p.Y1682–S1846; supporting). p.Glu428 is located in the N-terminal DExD helicase domain, far outside both PM1-eligible regions.	cspec
PM2	Met	NM_177438.2:c.1282G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with allele frequency < 0.000005, meeting the DICER1 VCEP PM2_Supporting threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not met	PM5 requires a different missense variant at the same residue (p.Glu428) classified as pathogenic by the ClinGen DICER1 VCEP. No such comparator exists — the variant is absent from ClinVar and no other missense change at p.Glu428 has been identified.	cspec clinvar
PM6	N/A	PM6 is not applicable under the DICER1 VCEP; de novo evidence is assessed exclusively through PS2.	cspec
PP1	Not assessed	No cosegregation data are available. No family studies or pedigrees involving NM_177438.2:c.1282G>C have been reported.
PP2	N/A	PP2 is not applicable under the DICER1 VCEP. Although DICER1 meets the missense constraint z-score threshold, the VCEP recommends against using PP2 due to the presence of multiple benign/likely benign missense variants in ClinVar.	cspec
PP3	Not met	The DICER1 VCEP requires REVEL ≥ 0.750 for PP3_Supporting in missense variants. The REVEL score for NM_177438.2:c.1282G>C is 0.186, well below the threshold. SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel (-0.262) also supports a benign computational profile.	revel bayesdel spliceai cspec
PP4	Not assessed	No somatic tumor testing data are available to evaluate for an RNase IIIb hotspot second hit with retention of the germline variant. PP4 requires tumor sequencing of a DICER1-associated neoplasm in a proband carrying this variant.
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP marks PP5 as Not Applicable.	cspec
BA1	Not met	BA1 requires allele frequency > 0.003 (0.3%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. NM_177438.2:c.1282G>C is absent from all gnomAD versions (v2.1, v4.1, Canada).	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	BS1 requires allele frequency > 0.0003 (0.03%) in gnomAD subpopulations with >2,000 alleles tested and ≥5 alleles present. NM_177438.2:c.1282G>C is absent from all gnomAD versions.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	No data are available regarding tumor-free females through age 50 or homozygosity observations for this variant.
BS3	Not assessed	No functional data are available to evaluate a benign effect. The BS3_Strong rule (RNA assay showing no splicing impact) is restricted to intronic or synonymous variants. The BS3_Supporting rule requires an in vitro cleavage assay demonstrating normal 5p/3p miRNA production, which has not been performed for this variant.	cspec
BS4	Not assessed	No family segregation data are available. BS4 requires phenotype-positive, genotype-negative first-, second-, or third-degree relatives of the proband.
BP1	N/A	BP1 is not applicable to DICER1 under the VCEP. Truncating variants account for only a portion of disease-causing variants in DICER1.	cspec
BP2	Not assessed	No data are available regarding observations of this variant in trans with a known P/LP DICER1 variant or in cis/phase unknown with multiple P/LP DICER1 variants.
BP4	Met	The DICER1 VCEP BP4 rule requires REVEL < 0.500 and agreement in splicing predictors that no splicing effects are predicted. REVEL is 0.186 (< 0.500) and SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel (-0.262) also supports a benign computational profile.	revel spliceai bayesdel cspec
BP5	N/A	BP5 is not applicable to DICER1 under the VCEP. Given the broad spectrum of DICER1-related neoplasms and the lack of evidence for other high-penetrance germline variants that could account for such neoplasms, this rule should not be used.	cspec
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The DICER1 VCEP marks BP6 as Not Applicable.	cspec
BP7	N/A	BP7 applies to silent/intronic/non-coding variants and requires the variant also meet BP4. NM_177438.2:c.1282G>C is a missense variant (p.Glu428Gln) and does not fall into any BP7-eligible variant class.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
PM3	N/A	DICER1-related tumor predisposition is autosomal dominant; PM3 (detected in trans for recessive disorders) is not applicable per the VCEP.	cspec
PM4	N/A	PM4 applies to in-frame indels and stop-loss variants; this is a missense substitution.

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