Classification rationale

PVS1PM2 Likely Pathogenic

DICER1 c.1708A>T

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.¹ 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).² 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).³

PVS1 + PM2 → Likely Pathogenic

1 cspec ↗pvs1_generic_framework ↗vcep_pvs1_decisiontree

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 final_classification_framework

Gene diagram · NM_177438.2 · variants mapped to exon structure

DICER1 NM_177438.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 11 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

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.

Nonsense variant producing p.Lys570Terwell upstream of the VCEP-specified NMD cutoff at p.Pro1850Exon 10 is present in the biologically-relevant transcript NM_177438.2

cspec ↗pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

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.

Variant is absent from gnomAD v2.1 (exomes)Variant is absent from gnomAD v4.1 (exomes/genomes)Variant is absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 PS1 under the DICER1 VCEP requires a same amino acid change previously classified as pathogenic by the ClinGen DICER1 VCEP.

PS2 No de novo observations are available for this variant.

PS4 No proband phenotype data or case reports are available for this variant.

PP1 No co-segregation data are available for this variant.

PP4 No somatic tumor testing data are available.

Benign

BA1 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.

BS1 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.

BS2 No healthy-adult observation data are available.

BS3 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.

BS4 No family segregation data are available.

BP2 No observations in trans or cis with known pathogenic/likely pathogenic DICER1 variants are available.

N/A · 15 PS3 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

20305640 ↗ Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. ONCOKB

21266384 ↗ DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. ONCOKB

21501861 ↗ Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. ONCOKB

22353998 ↗ Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice. ONCOKB