Variant classification summary

NM_177438.2:c.2536A>G

DICER1 · NP_803187.1:p.(Ile846Val) · NM_177438.2

GRCh37: chr14:95574331 T>C · GRCh38: chr14:95107994 T>C

Gene: DICER1 Transcript: NM_177438.2

Final call

VUS

BP4 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Ile846Val)

gnomAD AF

3.098984029075908e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): REVEL 0.191 is below the <0.500 threshold and SpliceAI predicts no splice impact (max delta 0.029).

2

VUS: with only BP4 Supporting applied (-1 pt), the DICER1 VCEP v1.4 total of -1 falls in Rule 3 (-1 to +5), yielding Uncertain Significance.

Final determination:

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	Not applicable: this is a missense change, and PVS1 applies only to null variants (nonsense/frameshift with NMD, canonical splice) under the DICER1 VCEP.	cspec
PS1	Not assessed	Not assessed: no DICER1 VCEP-asserted pathogenic variant producing the same p.Ile846Val amino acid change was available for comparison.	pm5_candidates
PS2	Not assessed	Not assessed: no de novo observation with confirmed maternity and paternity was available to score PS2.	cspec
PS3	Not assessed	Not assessed: no RNA/splicing or in vitro microRNA cleavage assay data for this variant was available.
PS4	Not assessed	Not assessed: no case series or phenotype data sufficient to assign phenotype points was available.	cspec PMID:38084291 clinvar
PM1	Not met	Not met: residue 846 lies outside the RNase IIIb domain (p.Y1682-p.S1846), the only region where the VCEP applies PM1.	cspec
PM2	Not met	Not met: gnomAD v4.1 allele frequency 3.1e-05 (50/1,613,432 alleles) exceeds the required <0.000005 threshold.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: DICER1 predisposition is autosomal dominant, so recessive trans-phase evidence (PM3) is not scored.	cspec
PM4	N/A	Not applicable: PM4 applies only to in-frame indels, and this is a single-nucleotide missense substitution.	cspec
PM5	Not assessed	Not assessed: no VCEP-asserted pathogenic missense at residue 846 with an equal or worse Grantham score was available.	pm5_candidates
PM6	N/A	Not applicable: the DICER1 VCEP directs de novo evidence to PS2 instead of PM6.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregation data were available to score PP1.	cspec
PP2	N/A	Not applicable: the DICER1 VCEP explicitly marks PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: REVEL 0.191 is far below the >=0.750 threshold, and SpliceAI predicts no splice impact (max delta 0.029).	cspec revel spliceai
PP4	Not assessed	Not assessed: no paired tumor sequencing demonstrating a somatic second hit with retention of this variant was available.	cspec PMID:38084291
PP5	N/A	Not applicable: excluded by the DICER1 VCEP, and the ClinVar record has no expert-panel submission.	cspec clinvar PMID:38084291
BA1	Not met	Not met: highest gnomAD subpopulation frequency is 5.0e-05 (Admixed American, 3/60,004), far below the >0.003 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: highest gnomAD subpopulation frequency 5.0e-05 does not reach the >0.0003 BS1 threshold.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no homozygotes were seen, but the required data on 10+ tumor-free unrelated females was unavailable.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no in vitro microRNA cleavage assay or RNA splicing data for this variant was available.
BS4	Not assessed	Not assessed: no phenotype-positive relatives with negative genotypes were available to assess lack of segregation.	cspec
BP1	N/A	Not applicable: the DICER1 VCEP explicitly marks BP1 as not applicable for this gene.	cspec
BP2	Not assessed	Not assessed: no in-trans or in-cis observations with pathogenic DICER1 variants were available.	cspec
BP3	N/A	Not applicable: the DICER1 VCEP explicitly marks BP3 as not applicable for this gene.	cspec
BP4	Met	Met (Supporting): REVEL 0.191 is below the <0.500 threshold and SpliceAI predicts no splice impact (max delta 0.029).	cspec revel spliceai
BP5	N/A	Not applicable: the DICER1 VCEP explicitly excludes BP5 for this gene.	cspec PMID:38084291
BP6	N/A	Not applicable: excluded by the DICER1 VCEP, and the ClinVar record lacks an expert-panel assertion.	cspec clinvar PMID:38084291
BP7	N/A	Not applicable: BP7 applies only to synonymous or non-coding variants, and this is a missense substitution.	cspec

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