Variant classification summary

NM_177438.2:c.1708A>T

DICER1 · NP_803187.1:p.(Lys570Ter) · NM_177438.2

GRCh37: chr14:95582834 T>A · GRCh38: chr14:95116497 T>A

Gene: DICER1 Transcript: NM_177438.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

DICER1

Transcript

NM_177438.2

Protein

NP_803187.1:p.(Lys570Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_177438.2:c.1708A>T (p.Lys570Ter) is a nonsense variant predicted to trigger nonsense-mediated decay, given its location 5' of the DICER1 NMD cutoff at p.Pro1850 per ClinGen DICER1 VCEP v1.4, meeting PVS1 at Very Strong strength.

2

The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting the DICER1 VCEP PM2_Supporting threshold (allele frequency <0.000005).

3

Under the Tavtigian point-based framework adopted by the DICER1 VCEP, PVS1_VeryStrong contributes 8 points and PM2_Supporting contributes 1 point, yielding a total of 9 points, which classifies this variant as Likely Pathogenic (range: 6 to 9 points).

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 9, which maps to Likely Pathogenic 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	Met	Nonsense variant NM_177438.2:c.1708A>T produces a premature termination codon at p.Lys570 (K570*), which lies well 5' of the DICER1 NMD cutoff at p.Pro1850 specified by the ClinGen DICER1 VCEP v1.4. The variant is predicted to trigger nonsense-mediated decay, resulting in complete loss of function.	cspec pvs1_generic_framework vcep_pvs1_decisiontree
PS1	Not met	PS1 under the DICER1 VCEP requires a same amino acid change previously classified as pathogenic by the ClinGen DICER1 VCEP. No other nucleotide change producing p.Lys570Ter with VCEP-classified pathogenicity has been identified; the variant is absent from ClinVar entirely.	cspec clinvar
PS2	Not assessed	No de novo observations are available for this variant. The DICER1 VCEP requires de novo point tallying from confirmed parent-proband trios; no such data were identified in ClinVar or the literature for NM_177438.2:c.1708A>T.
PS3	N/A	The DICER1 VCEP v1.4 instructions state: 'Do not apply PS3 at any strength if PVS1 is applied at full strength.' PVS1 is assessed at Very Strong (full strength) for this nonsense variant; therefore PS3 is not applicable per VCEP rules.	cspec
PS4	Not assessed	No proband phenotype data or case reports are available for this variant. PS4 requires phenotype points from unrelated probands with DICER1-associated tumors; the variant is absent from ClinVar and no case observations were identified in the literature.
PS5	N/A	Not a standard ACMG/AMP criterion. There is no PS5 code in the ACMG/AMP guidelines; this was likely intended as PP5, which is assessed separately and is Not Applicable per the DICER1 VCEP.
PM1	N/A	The DICER1 VCEP restricts PM1 to missense variants at specific residues: Moderate for metal ion-binding codons (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813) and Supporting for other residues in the RNase IIIb domain (p.Y1682-p.S1846). This is a nonsense variant at p.570, far outside both the RNase IIIb domain and the metal ion-binding codons.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the DICER1 VCEP PM2_Supporting threshold of allele frequency <0.000005 with no more than one allele in any subpopulation.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	The DICER1 VCEP PM5 rule applies to missense variants at an amino acid residue where a different missense change has been classified as pathogenic. This variant is a nonsense substitution (p.Lys570Ter), not a missense change, and the pm5_candidates.json confirms the variant class is not compatible with PM5.	cspec pm5_candidates
PM6	N/A	The DICER1 VCEP has combined PM6 with PS2 and recommends using PS2 exclusively for de novo evidence. PM6 is marked as Not Applicable by the VCEP.
PP1	Not assessed	No co-segregation data are available for this variant. PP1 requires observation across multiple meioses in families with DICER1-associated phenotypes; no such data were identified.
PP2	N/A	The DICER1 VCEP explicitly states PP2 is not applicable for DICER1: despite meeting the missense constraint z-score threshold, the VCEP recommends against its use due to the presence of benign/likely benign missense variants throughout the gene in ClinVar.
PP3	N/A	The DICER1 VCEP PP3 rule applies only to missense variants (REVEL >= 0.750) or splicing variants (concordance of MaxEntScan and SpliceAI). This is a nonsense variant, not a missense or splicing variant; no splicing impact is predicted (SpliceAI max delta = 0.00). PP3 does not apply.	cspec spliceai
PP4	Not assessed	No somatic tumor testing data are available. The DICER1 VCEP PP4 requires identification of a somatic hotspot second hit in an RNase IIIb codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) with retention of the germline variant. No tumor sequencing results were provided.
PP5	N/A	PP5 is marked as 'Not Applicable for this VCEP' by the ClinGen DICER1 VCEP per recommendations of the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	The DICER1 VCEP BA1 threshold requires allele frequency >0.003 (0.3%) in a gnomAD subpopulation with >2,000 alleles tested and minimum 5 alleles present. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The DICER1 VCEP BS1 threshold requires allele frequency >0.0003 (0.03%) in a gnomAD subpopulation with >2,000 alleles tested and minimum 5 alleles present. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No healthy-adult observation data are available. The DICER1 VCEP BS2 requires 40+ tumor-free females through age 50 (Strong) or 10+ (Supporting), or homozygosity observations. No such population or clinical data were identified for this variant.
BS3	Not met	The DICER1 VCEP BS3 applies to intronic/synonymous variants with RNA evidence of no splicing impact, or variants with in vitro cleavage assays demonstrating normal miRNA production. No functional studies have been performed on NM_177438.2:c.1708A>T; the four publications reviewed discuss DICER1 at the gene level only and do not test this variant.
BS4	Not assessed	No family segregation data are available. BS4 requires phenotype-positive, genotype-negative relatives of the proband; no familial testing data were identified.
BP1	N/A	The DICER1 VCEP marks BP1 as Not Applicable: truncating variants account for only a portion of disease-causing variants in DICER1, so the BP1 logic (missense in a gene where primarily truncating variants cause disease) does not apply.
BP2	Not assessed	No observations in trans or cis with known pathogenic/likely pathogenic DICER1 variants are available. BP2 requires at least 1 observation in trans with a P/LP variant or 3+ observations in cis/phase-unknown with 2+ different P/LP variants.
BP4	N/A	The DICER1 VCEP BP4 rule applies to missense variants (REVEL < 0.500 with no splicing predicted) or synonymous/intronic/non-coding variants (concordance of MaxEntScan and SpliceAI). This is a nonsense variant and falls outside the VCEP scope for BP4.	cspec spliceai
BP5	N/A	The DICER1 VCEP marks BP5 as Not Applicable: given the broad spectrum of DICER1-related neoplasms and lack of evidence of other high-penetrance germline variants that could account for such neoplasms, this rule should not be used at this time.
BP6	N/A	BP6 is marked as 'Not Applicable for this VCEP' by the ClinGen DICER1 VCEP per recommendations of the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	N/A	The DICER1 VCEP BP7 rule applies only to silent variants, intronic variants at or beyond +7 to -21 positions, or other non-coding variants meeting conservation criteria. This is a nonsense variant and does not qualify.
BP3	N/A	In-frame deletions/insertions in a repetitive region — not applicable to a substitution variant.
PM3	N/A	DICER1 is autosomal dominant; PM3 for recessive disorders is not applicable.
PM4	N/A	Protein length changes from in-frame indels or stop-loss — not applicable to a nonsense substitution.

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