Variant classification summary

NM_177438.2:c.3334A>G

DICER1 · NP_803187.1:p.(Asn1112Asp) · NM_177438.2

GRCh37: chr14:95570399 T>C · GRCh38: chr14:95104062 T>C

Gene: DICER1 Transcript: NM_177438.2

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Asn1112Asp)

gnomAD AF

5.575897254799918e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.2:c.3334A>G (p.Asn1112Asp) is a missense variant in exon 21 of DICER1, located outside the RNase IIIb catalytic domain (p.Y1682-p.S1846) and not at a metal ion-binding residue.

2

This variant is present in gnomAD at a frequency exceeding the DICER1 VCEP threshold for rarity. In the East Asian population, the allele frequency is 0.098% (gnomAD v2.1, 18/18,382 alleles) and 0.198% (gnomAD v4.1, 89/44,880 alleles), meeting BS1 at strong strength (VCEP threshold: >0.03%).

3

Computational predictions uniformly support a benign interpretation: REVEL score 0.109 (below BP4 threshold of <0.500), SpliceAI max delta 0.09 (no splicing impact), and BayesDel score -0.562 (benign). BP4 is met at supporting strength.

4

In ClinVar, this variant has been classified as Likely benign by three clinical laboratories (Ambry Genetics, Labcorp/Invitae, Illumina) and as Uncertain significance by one (GeneDx). No expert panel has reviewed this variant. The ITMI submission derived from a reference population cohort (Bodian et al. 2014), consistent with a benign population variant.

5

No functional studies, segregation data, de novo observations, or tumor testing data are available for this variant. No pathogenic comparator variants exist at codon 1112 for PM5 application. The variant falls outside characterized functional domains, so PM1 does not apply.

6

Applying the DICER1 VCEP v1.4 Tavtigian point-based classification framework: BS1_Strong (-4 points) + BP4_Supporting (-1 point) = -5 points. This falls within the Likely Benign range (>= -6 and <= -2).

7

Final classification: Likely Benign.

Final determination: Per DICER1 VCEP v1.4 Tavtigian point-based rules: total score of -5 falls within the Likely Benign range (>= -6 and <= -2). The special override for a score of -1 does not apply.

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.3334A>G is a missense variant (p.Asn1112Asp), not a null variant (nonsense, frameshift, or canonical splice). The DICER1 VCEP PVS1 rules apply exclusively to nonsense, frameshift, and canonical splice variants. Missense variants do not qualify for PVS1.	cspec
PS1	Not met	No different nucleotide change at c.3334 resulting in the same amino acid change (p.Asn1112Asp) has been classified as pathogenic by the ClinGen DICER1 VCEP. Per VCEP rules, PS1 requires a comparator variant asserted as pathogenic by the DICER1 VCEP at the same amino acid position.	cspec clinvar
PS2	Not met	No de novo observations have been reported for NM_177438.2:c.3334A>G (p.Asn1112Asp). The DICER1 VCEP requires de novo points tallied from confirmed de novo events with DICER1-related phenotypes; none are available.
PS3	Not met	No functional studies (RNA splicing assay or in vitro cleavage assay) have been reported for p.Asn1112Asp. Computationally, REVEL score 0.109 and SpliceAI max delta 0.09 do not predict a deleterious effect. N1112 is outside the RNase IIIb catalytic domain and is not a metal ion-binding residue. No experimental evidence supports a damaging effect on DICER1 function.	revel spliceai bayesdel
PS4	Not met	No probands with DICER1-related tumor predisposition phenotypes have been reported to carry this variant. The variant has been observed in ClinVar with 3 clinical laboratories classifying it as Likely benign and 1 as Uncertain significance. The Bodian et al. 2014 cohort (PMID:24728327) identified this variant in a healthy population screen, consistent with a benign interpretation rather than enrichment in affected individuals. The ITMI submission also derives from a reference population. No phenotype points can be assigned under the DICER1 VCEP PS4 rubric.	clinvar PMID:24728327
PS5	Not met	PS5 is not included in the DICER1 VCEP criteria specification. Even under generic ACMG/AMP, PS5 would require a reputable source to have recently reported the variant as pathogenic with evidence unavailable for independent evaluation; ClinVar reports this variant as Likely benign, not pathogenic.	clinvar
PM1	Not met	p.Asn1112 is not located within the RNase IIIb domain (p.Y1682-p.S1846) and is not one of the seven metal ion-binding hotspot residues (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) per the DICER1 VCEP PM1 specification. The variant lies in a region with no known critical functional domain.	cspec
PM2	Not met	This variant is present in gnomAD v2.1 at an overall allele frequency of 0.00718% (18/250,782 alleles) and gnomAD v4.1 at 0.00558% (90/1,614,090 alleles), both exceeding the DICER1 VCEP PM2_Supporting threshold of <0.0005%. The East Asian subpopulation has 18 alleles in v2.1 and 89 in v4.1, far exceeding the 'no more than one allele in any subpopulation' requirement.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at codon 1112 has been classified by the ClinGen DICER1 VCEP for comparison. The PM5 candidates search returned zero same-residue comparator variants. Per VCEP PM5 rules, a comparator must be interpreted as pathogenic by the DICER1 VCEP with equal or worse Grantham score, which cannot be satisfied without an eligible comparator.	pm5_candidates cspec
PM6	N/A	PM6 is combined with PS2 per the DICER1 VCEP specification; the expert panel has opted to drop PM6 and exclusively use PS2 for de novo evidence. Assessed under PS2 instead.	cspec
PP1	Not met	No co-segregation data are available for this variant. No family studies reporting segregation of p.Asn1112Asp with DICER1-related phenotypes have been identified in the literature or ClinVar submissions.
PP2	N/A	PP2 is not applicable per the DICER1 VCEP. Despite DICER1 meeting the missense constraint Z-score cutoff (4.23 on gnomAD), the VCEP recommends this rule not be used due to the presence of numerous missense variants throughout the gene clinically interpreted as benign (9) or likely benign (30) in ClinVar.	cspec
PP3	Not met	REVEL score of 0.109 is well below the DICER1 VCEP PP3 threshold of >=0.750. SpliceAI predicts no splicing impact (max delta 0.09). BayesDel score of -0.562 corroborates a benign prediction. Multiple computational lines of evidence suggest no deleterious effect.	revel spliceai bayesdel
PP4	Not met	No somatic tumor testing data are available for a proband carrying this germline variant. The DICER1 VCEP PP4 rule requires demonstration of a somatic second hit at a known RNase IIIb hotspot codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) with retention of the germline variant. Such data are absent.
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the DICER1 VCEP specification. Even under generic ACMG/AMP, this variant is classified as Likely benign by multiple clinical laboratories, not pathogenic.	cspec clinvar
BA1	Not met	The highest subpopulation allele frequency is in East Asians at 0.098% (gnomAD v2.1, 18/18,382 alleles) and 0.198% (gnomAD v4.1, 89/44,880 alleles), both below the DICER1 VCEP BA1 threshold of >0.3%. While the Korean sub-subpopulation (EAS_KOR) reaches 0.394% in v2.1, the VCEP typically evaluates major continental subpopulations. Using the most comprehensive gnomAD version (v4.1), the EAS frequency remains below the BA1 cutoff.	gnomad_v2 gnomad_v4
BS1	Met	The East Asian population allele frequency of 0.098% (gnomAD v2.1, 18/18,382 alleles) and 0.198% (gnomAD v4.1, 89/44,880 alleles) exceeds the DICER1 VCEP BS1 threshold of >0.03%. The subpopulation has >2,000 alleles tested and >5 alleles present, satisfying all BS1 requirements at strong strength.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on healthy adult carriers meeting the DICER1 VCEP BS2 criteria. The variant has been observed in gnomAD in heterozygous state (0 homozygotes), but no study has specifically documented 40+ unrelated tumor-free females through age 50, nor are there confirmed homozygous healthy individuals.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no damaging effect on DICER1 splicing or pre-miRNA cleavage have been performed for p.Asn1112Asp. The DICER1 VCEP BS3 rule requires RNA assay data (no splicing impact, observed more than once) or in vitro cleavage assay showing normal 5p/3p miRNA production. Neither is available. Computational predictions alone (REVEL 0.109, SpliceAI max delta 0.09) do not satisfy BS3 which requires experimental functional evidence.	revel spliceai
BS4	Not met	No family segregation data are available for this variant. BS4 under the DICER1 VCEP requires phenotype-positive, genotype-negative 1st/2nd/3rd degree relatives with high- or moderate-specificity phenotypes. No such data have been reported.
BP1	N/A	BP1 is not applicable per the DICER1 VCEP. Truncating variants account for only a portion of disease-causing variants in DICER1, and missense variants (particularly in the RNase IIIb domain) are an established disease mechanism.	cspec
BP2	Not met	No observations of this variant in trans with a P/LP DICER1 variant have been reported. The DICER1 VCEP BP2 rule requires at least one observation in trans with a P/LP DICER1 variant (or >=3 in cis/phase unknown with 2+ different P/LP variants). No such data exist.
BP4	Met	REVEL score of 0.109 is well below the DICER1 VCEP BP4 threshold of <0.500, and SpliceAI predicts no splicing impact (max delta score 0.09). The agreement of multiple in silico predictors supports a benign interpretation.	revel spliceai bayesdel
BP5	N/A	BP5 is not applicable per the DICER1 VCEP. Given the broad spectrum of DICER1-related neoplasms and the lack of evidence of other high-penetrance germline variants that could account for such neoplasms, the VCEP recommends this rule not be used at this time.	cspec
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the DICER1 VCEP specification.	cspec
BP7	N/A	BP7 applies only to silent (synonymous) variants, deep intronic variants (at or beyond +7/-21 positions), or non-coding variants where the reference nucleotide is conserved across >=1 primate and/or >=4 mammalian species. NM_177438.2:c.3334A>G is a missense variant (p.Asn1112Asp) and does not meet any BP7 eligibility criteria.	cspec
BP3	N/A	Missense substitution; BP3 applies only to in-frame deletions/insertions in repetitive regions without known function.
PM3	N/A	DICER1-related tumor predisposition is autosomal dominant; PM3 applies to recessive disorders only.
PM4	N/A	Missense substitution; PM4 applies only to in-frame deletions/insertions and stop-loss variants.

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