DICER1c.1708A>TLikely pathogenic

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Variant interpretation report

DICER1 c.1708A>T, p.(Lys570Ter)

NM_177438.2:c.1708A>T NP_803187.1:p.(Lys570Ter) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About DICER1

No gene-level summary was recorded for this case.

Key facts

Condition: DICER1-related tumor predisposition
Inheritance: Autosomal dominant
Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen DICER1 VCEP v1.4
Pipeline record: 19 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen DICER1 VCEP v1.4. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen DICER1 VCEP v1.4, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 4 not met · 7 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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).

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).

Met · 2

PVS1 Very strongNonsense 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. Details ▾Hide ▴

Evidence considered

Nonsense variant producing p.Lys570Ter
well upstream of the VCEP-specified NMD cutoff at p.Pro1850
Exon 10 is present in the biologically-relevant transcript NM_177438.2
DICER1 loss-of-function is an established disease mechanism for germline tumor predisposition (autosomal dominant
MONDO:0100216)

Sources

cspec ↗pvs1_generic_framework ↗vcep_pvs1_decisiontree

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

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
Allele frequency = 0.0
well below the VCEP PM2 threshold of <0.000005

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Not met · 4 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Evidence considered

No ClinVar entries exist for any p.Lys570Ter variant from a different nucleotide change

Sources

cspec ↗clinvar ↗

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. The variant is absent from all gnomAD populations. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD across all populations

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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. The variant is absent from all gnomAD populations. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD across all populations

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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. 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. Details ▾Hide ▴

Still missing

No functional data available for this variant

Not assessed · 7 · no assessment recorded

PS2 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. Details ▾Hide ▴

Still missing

No de novo segregation data available in the case materials

PS4 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. Details ▾Hide ▴

Still missing

No proband phenotype data available to tally phenotype points

PP1 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. Details ▾Hide ▴

Still missing

No family segregation data available

PP4 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. Details ▾Hide ▴

Still missing

No tumor sequencing data available to assess somatic second-hit status

BS2 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. Details ▾Hide ▴

Still missing

No healthy adult carrier data available

BS4 No family segregation data are available. BS4 requires phenotype-positive, genotype-negative relatives of the proband; no familial testing data were identified. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 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. Details ▾Hide ▴

Still missing

No phase information or co-occurrence data available

Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴

PS3 N/AThe 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. Details ▾Hide ▴

Sources

cspec ↗

PM1 N/AThe 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. Details ▾Hide ▴

Evidence considered

Nonsense variant at p.570
PM1 is restricted to missense variants at specified residues per VCEP

Sources

cspec ↗

PM3 VCEPDICER1 is autosomal dominant; PM3 for recessive disorders is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AProtein length changes from in-frame indels or stop-loss — not applicable to a nonsense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThe 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. Details ▾Hide ▴

Sources

cspec ↗pm5_candidates

PM6 VCEPThe 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. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPThe 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. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AThe 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00
no splicing impact predicted
VCEP PP3 is restricted to missense and splicing variants

Sources

cspec ↗spliceai ↗

PP5 VCEPPP5 is marked as 'Not Applicable for this VCEP' by the ClinGen DICER1 VCEP per recommendations of the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPThe 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. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPIn-frame deletions/insertions in a repetitive region — not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/AThe 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00
no splicing impact predicted
VCEP BP4 is restricted to missense and synonymous/intronic/non-coding variants

Sources

cspec ↗spliceai ↗

BP5 VCEPThe 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. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked as 'Not Applicable for this VCEP' by the ClinGen DICER1 VCEP per recommendations of the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThe 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. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANot 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: DICER1
Transcript: NM_177438.2
Coding (HGVS c.): NM_177438.2:c.1708A>T
Protein (HGVS p.): NP_803187.1:p.(Lys570Ter)
GRCh38: chr14:95116497 T>A
GRCh37: chr14:95582834 T>A

Gene diagram

Every interpreted variant in DICER1, mapped onto the exon structure of NM_177438.2. Select a row to find it on the plot.

DICER1NM_177438.2

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in DICER1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: 0.660

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.00
no splicing impact predicted
VCEP PP3 is restricted to missense and splicing variants

Sources

cspec ↗spliceai ↗

Evidence considered

SpliceAI max delta score = 0.00
no splicing impact predicted
VCEP BP4 is restricted to missense and synonymous/intronic/non-coding variants

Sources

cspec ↗spliceai ↗

No further detail was recorded.

Statement

In silico

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

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia.

Reports that Dicer1 deletion in mouse osteoprogenitors disrupts hematopoiesis and induces myelodysplasia. NM_177438.2:c.1708A>T was not identified in this paper.
Does not name this variant
PMID 20305640 ↗
DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome.

Sequenced DICER1 in constitutional DNA from 823 patients with tumors and 781 cancer cell lines, identifying constitutional DICER1 mutations in familial PPB and related tumors. NM_177438.2:c.1708A>T was not mentioned in the abstract.
Does not name this variant
PMID 21266384 ↗
Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry.

Characterizes ovarian sex cord-stromal tumors in PPB kindreds and their association with germline DICER1 mutations. NM_177438.2:c.1708A>T was not identified in the full text.
Does not name this variant
PMID 21501861 ↗
Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice.

Reports that Dicer1 deletion in murine myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development. NM_177438.2:c.1708A>T was not mentioned in the abstract.
Does not name this variant
PMID 22353998 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

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

Functional

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.