Variant classification summary

NM_177438.3:c.2997T>G

DICER1 · NP_803187.1:p.(Leu999=) · NM_177438.3

GRCh37: chr14:95572111 A>C · GRCh38: chr14:95105774 A>C

Gene: DICER1 Transcript: NM_177438.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 supporting benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

DICER1

Transcript

NM_177438.3

Protein

NP_803187.1:p.(Leu999=)

gnomAD AF

0.003102553425635382 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.3:c.2997T>G (p.Leu999=) is a synonymous variant in exon 19 of DICER1. It is present at high frequency in gnomAD v4.1 with an overall allele frequency of 0.31% (5007/1613832 alleles) and 121 homozygotes. The highest subpopulation frequency is 5.69% in African/African American individuals (4272/75026 alleles, 116 homozygotes), exceeding the VCEP BA1 stand-alone benign threshold of >0.3%.

2

BA1 (Stand-Alone Benign) is met: the African/African American subpopulation allele frequency of 5.69% exceeds the 0.3% threshold with >2000 alleles tested and ≥5 alleles present. A frequency of this magnitude is incompatible with a highly penetrant autosomal dominant tumor predisposition disorder.

3

BS1 (Strong Benign) is independently met at the >0.03% threshold in the same subpopulation, subsumed by the stronger BA1 evidence.

4

BS2_Supporting is met: 121 homozygous individuals are reported in gnomAD v4.1, satisfying the VCEP threshold of ≥2 homozygotes in individuals lacking clinical information.

5

BP4_Supporting is met: SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.03).

6

BP7_Supporting is met: the variant is a synonymous change (p.Leu999=) and meets BP4, satisfying the DICER1 VCEP BP7 requirements.

7

This variant has been classified as Benign by 10 clinical laboratories in ClinVar (VariationID: 261920), consistent with the population frequency evidence.

8

No publications among the seven reviewed (PMID:25741868, 26467025, 24493721, 29474644, 24761742, 25394175, 28492532) specifically mention NM_177438.3:c.2997T>G or p.Leu999=. All are methodology, guideline, or gene-level review papers without variant-specific evidence.

9

Under the Tavtigian point-based system (DICER1 VCEP v1.4.0): BA1 = -8 points. BS2_Supporting = -1 point. BP4_Supporting = -1 point. BP7_Supporting = -1 point. Total = -11 points. Classification: Benign (≤ -7).

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 -15, which maps to Benign 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_177438.3:c.2997T>G is a synonymous variant (p.Leu999=) in exon 19. VCEP PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2, initiation codon, exon deletion). This variant does not alter the amino acid sequence and is not a null variant.	pvs1_variant_assessment cspec
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic missense variant. This is a synonymous variant (p.Leu999=) with no amino acid change; there is no comparator pathogenic missense at this codon under the VCEP rule.	cspec
PS2	Not met	No de novo observations identified for NM_177438.3:c.2997T>G in any reviewed publication or ClinVar submission. The variant is common in population databases (gnomAD homozygote count = 121 in v4.1), which is inconsistent with a highly penetrant de novo variant.	gnomad_v4
PS3	Not met	No well-established in vitro or in vivo functional studies (RNA splicing assay or cleavage assay) have been performed for this specific variant. The reviewed publications are methodology or guideline papers that do not report functional data for NM_177438.3:c.2997T>G.
PS4	N/A	Per DICER1 VCEP v1.4.0: 'Do not apply PS4 if variant meets BA1/BS1 criteria.' BA1 and BS1 are both met (African/African American AF = 5.69% in gnomAD v4.1). The variant is too common in the general population for PS4 to be applicable.	cspec gnomad_v4
PS5	N/A	PS5 is not a criterion defined by the DICER1 VCEP v1.4.0 nor by standard ACMG/AMP 2015 guidelines. This criterion code is not in use.
PM1	N/A	PM1 applies to missense variants at specific functional residues (metal ion-binding codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813 for moderate; RNase IIIb domain for supporting). This is a synonymous variant, not a missense change.	cspec
PM2	Not met	Per DICER1 VCEP: PM2_Supporting requires allele frequency <0.000005 across gnomAD. This variant has AF = 0.00310 (0.31%) in gnomAD v4.1 and AF = 0.00564 (0.56%) in gnomAD v2.1, far exceeding the threshold. Highest subpopulation AF = 5.69% (African/African American, gnomAD v4.1).	gnomad_v4 gnomad_v2
PM5	N/A	PM5 requires a missense variant at a residue where a different pathogenic missense has been observed. This is a synonymous variant (p.Leu999=) with no amino acid change. Per pm5_candidates.json: 'Framework is classic same-residue missense PM5, but the variant class is not missense-like.'	pm5_candidates cspec
PM6	N/A	Per DICER1 VCEP v1.4.0: PM6 is Not Applicable. The VCEP has combined PM6 with PS2 and uses PS2 exclusively for de novo evidence.	cspec
PP1	N/A	Per DICER1 VCEP v1.4.0: 'Do not apply PP1 if variant meets BA1/BS1 criteria.' BA1 and BS1 are both met. Segregation analysis is contraindicated for a variant this common in the general population.	cspec gnomad_v4
PP2	N/A	Per DICER1 VCEP v1.4.0: PP2 is Not Applicable. The VCEP states: 'While DICER1 does meet recommended cutoff for missense constraint z score... the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign or likely benign in ClinVar.'	cspec
PP3	Not met	Per DICER1 VCEP: PP3_Supporting requires REVEL ≥ 0.750 for missense variants OR agreement in splicing predictors predicting splicing effects. This variant is synonymous (REVEL not applicable) and SpliceAI max delta = 0.03 predicts no splicing impact. No evidence of a deleterious effect on the gene product.	spliceai cspec
PP4	Not met	No somatic tumor testing data available demonstrating a DICER1 somatic hotspot second hit (at p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) with retention of the germline variant. No tumor sequencing data identified.
PP5	N/A	Per DICER1 VCEP v1.4.0: PP5 is Not Applicable. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Met	NM_177438.3:c.2997T>G has an allele frequency of 5.69% in the African/African American population in gnomAD v4.1 (4272/75026 alleles, 116 homozygotes), exceeding the DICER1 VCEP BA1 threshold of >0.3% in a subpopulation with >2000 alleles and ≥5 alleles present. This frequency is incompatible with a highly penetrant autosomal dominant tumor predisposition syndrome.	gnomad_v4 gnomad_v2 cspec
BS1	Met	The African/African American subpopulation AF of 5.69% in gnomAD v4.1 exceeds the DICER1 VCEP BS1 threshold of >0.03% with >2000 alleles and ≥5 alleles present. This criterion is independently met but subsumed by BA1.	gnomad_v4 gnomad_v2 cspec
BS2	Met	Per DICER1 VCEP BS2_Supporting: '2+ observations of homozygosity in individuals lacking clinical information.' gnomAD v4.1 reports 121 homozygotes for NM_177438.3:c.2997T>G. The presence of numerous homozygous individuals in a population database is inconsistent with a pathogenic dominant tumor predisposition variant.	gnomad_v4 gnomad_v2 cspec
BS3	Not met	Per DICER1 VCEP BS3_Strong: requires 'no splicing impact observed via RNA assay (observed more than once).' No RNA assay data is available for this variant. SpliceAI predicts no splicing effect (delta = 0.03) but this is in silico prediction, not functional RNA data. BS3_Supporting requires a cleavage assay demonstrating normal microRNA production, which has not been performed.	spliceai
BS4	Not met	No segregation data available. No evidence of phenotype-positive, genotype-negative first-, second-, or third-degree relatives of a proband carrying this variant.
BP1	N/A	Per DICER1 VCEP v1.4.0: BP1 is Not Applicable. The VCEP states: 'This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.'	cspec
BP2	Not met	No observations of NM_177438.3:c.2997T>G in trans with a pathogenic/likely pathogenic DICER1 variant, nor in cis with 2+ different P/LP DICER1 variants, in any reviewed data source.
BP4	Met	Per DICER1 VCEP: for synonymous variants, concordance of MaxEntScan and SpliceAI showing no splicing effects qualifies for BP4_Supporting. SpliceAI predicts no splicing impact (max delta score = 0.03). This synonymous change at c.2997T>G is not predicted to create a cryptic splice site or disrupt splicing.	spliceai cspec
BP5	N/A	Per DICER1 VCEP v1.4.0: BP5 is Not Applicable. The VCEP states: '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, this rule should not be used at this time.'	cspec
BP6	N/A	Per DICER1 VCEP v1.4.0: BP6 is Not Applicable. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	Met	NM_177438.3:c.2997T>G is a synonymous (silent) variant (p.Leu999=). Per DICER1 VCEP BP7_Supporting: 'Silent variant... Caveat: Variant must meet BP4 to apply BP7.' BP4 is met (SpliceAI predicts no splicing impact, delta = 0.03). This variant does not alter the amino acid sequence and is not predicted to affect splicing.	spliceai cspec

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