NM_177438.2:c.1468C>T

DICER1 · NP_803187.1:p.(Arg490Cys) · NM_177438.2

GRCh37: chr14:95584000 G>A · GRCh38: chr14:95117663 G>A

Gene: DICER1 Transcript: NM_177438.2

Final call

VUS

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Arg490Cys)

gnomAD AF

2.7262070281617187e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_177438.2:c.1468C>T (p.Arg490Cys) is a missense variant in exon 9 of DICER1.

This variant is present in gnomAD v4.1 at an overall allele frequency of 2.73e-05 (44/1,613,964 alleles) and at 3.18e-05 in v2.1 (9/282,736 alleles), with the highest subpopulation frequency in South Asians (v4.1: 0.00011). No homozygotes have been observed.

The variant does not meet the VCEP PM2 threshold (AF < 5.0e-06 with ≤1 allele per subpopulation), as the overall frequency exceeds this cutoff and multiple alleles are present in the South Asian subpopulation.

The variant has been reported in ClinVar (Variation ID 242039) as Uncertain significance by multiple clinical laboratories and as Likely benign by one submitter; review status is 'criteria provided, single submitter' with no expert panel classification.

The variant was observed as a somatic finding in one pineoblastoma tumor (RBTC779, MYC subgroup) without evident loss of heterozygosity, described as 'potentially deleterious' in a study of pineoblastoma molecular subgroups.

Computational predictors are indeterminate: REVEL score is 0.502 (borderline; VCEP PP3 requires ≥0.750, BP4 requires <0.500), SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel score is 0.158.

The variant is located at p.Arg490, which lies outside the VCEP-defined metal ion-binding residues and RNase IIIb domain; it is not in a statistically significant cancer hotspot.

No functional studies, de novo observations, segregation data, or tumor second-hit data were identified that would support application of any pathogenic or benign criterion at any strength level under the ClinGen DICER1 VCEP v1.4.0 framework.

Under the VCEP Tavtigian point-based system, no criteria are met in either the pathogenic or benign direction, yielding a total point value of 0, which classifies as Uncertain Significance (Rule3: -1 to 5 points).

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 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	This is a missense substitution (p.Arg490Cys). VCEP PVS1 rules apply only to nonsense, frameshift, and canonical splice site variants. The variant does not fall into any PVS1 null-variant bucket.	cspec
PS1	Not met	PS1 requires a different nucleotide change at the same amino acid position previously classified as pathogenic by the ClinGen DICER1 VCEP. No such comparator variant was identified.	cspec
PS2	Not met	No de novo observations were identified in the literature or ClinVar submissions for this variant. VCEP PS2 requires documented de novo events with confirmed parentage.
PS3	Not met	No functional studies (RNA assay, in vitro cleavage assay, or other validated functional data) were identified for this variant. SpliceAI predicts no splicing impact (max delta = 0.00). OncoKB reports no variant-specific functional evidence.	spliceai oncokb
PS4	Not met	No variant-specific proband counts or phenotype points meeting VCEP PS4 thresholds were identified. The variant was observed as a somatic finding in one pineoblastoma tumor (PMID:31820118) but this does not constitute independent germline proband evidence.	PMID:31820118
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not included in the ClinGen DICER1 VCEP v1.4.0 specifications.
PM1	Not met	The variant is at p.Arg490, which lies outside the VCEP-defined metal ion-binding residues (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) and outside the RNase IIIb domain (p.Y1682–p.S1846). The residue is not in a statistically significant cancer hotspot.	cspec
PM2	Not met	gnomAD v4.1 overall AF = 2.73e-05 exceeds the VCEP PM2 threshold of <5.0e-06. Additionally, 10 alleles are present in the South Asian subpopulation (AF = 0.00011), violating the 'no more than one allele in any subpopulation' requirement.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No pathogenic missense comparator at the same residue (p.Arg490) classified by the ClinGen DICER1 VCEP was identified. PM5 candidate search returned zero same-residue candidates.	cspec
PM6	N/A	VCEP combines PM6 with PS2 and directs use of PS2 exclusively for de novo evidence. Per VCEP v1.4.0, PM6 is not applicable.	cspec
PP1	Not met	No co-segregation data across affected family members were identified. VCEP PP1 requires at least 3–4 meioses for supporting-level evidence.
PP2	N/A	VCEP recommends PP2 not be used for DICER1 due to the presence of multiple benign/likely benign missense variants in ClinVar despite a high missense constraint z-score.	cspec
PP3	Not met	REVEL score = 0.502, which is below the VCEP PP3 threshold of ≥0.750. SpliceAI predicts no splicing impact (max delta = 0.00). Neither computational criterion for pathogenicity is satisfied.	revel spliceai cspec
PP4	Not met	VCEP PP4 requires somatic tumor testing demonstrating a known RNase IIIb hotspot second hit in a DICER1-associated neoplasm, with retention of the germline variant. No such tumor testing data were provided for this case.	cspec
PP5	N/A	VCEP declares PP5 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	Highest gnomAD subpopulation AF is 0.00011 (South Asian, v4.1), far below the VCEP BA1 threshold of >0.003 (0.3%).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Highest gnomAD subpopulation AF is 0.00011 (South Asian, v4.1), below the VCEP BS1 threshold of >0.0003 (0.03%) and with fewer than the minimum 5 alleles required in the v2.1 SAS subpopulation (3 alleles).	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No data on tumor-free females through age 50 or homozygous observations in healthy individuals were available for this variant.
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect on DICER1 protein function or splicing were identified for this variant.
BS4	Not met	No segregation data demonstrating phenotype-positive, genotype-negative relatives were identified. VCEP BS4 requires affected relatives who are genotype-negative.
BP1	N/A	VCEP declares BP1 not applicable for DICER1 because truncating variants account for only a portion of disease-causing variants.	cspec
BP2	Not met	No observations of this variant in trans with a P/LP DICER1 variant or in cis/phase unknown with multiple P/LP DICER1 variants were identified.
BP4	Not met	REVEL score = 0.502, which is not < 0.500 as required by VCEP BP4 for missense variants. Although SpliceAI predicts no splicing impact, the REVEL score does not satisfy the BP4 threshold.	revel spliceai cspec
BP5	N/A	VCEP declares BP5 not applicable due to the broad spectrum of DICER1-related neoplasms and lack of evidence for alternative high-penetrance germline variants.	cspec
BP6	N/A	VCEP declares BP6 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies to silent, intronic, or non-coding variants. This is a missense substitution (p.Arg490Cys) and does not qualify. Additionally, BP7 requires BP4 to be met, which it is not.	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 (in trans with pathogenic variant) is not applicable.	cspec
PM4	N/A	PM4 applies to in-frame indels and stop-loss variants. This is a missense substitution.

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