Classification rationale

BA1BS1BS2 Benign

DICER1 c.1510-4dup unknown · exon 9i

Benign: BA1 is stand-alone because the African/African American gnomAD v4.1 allele frequency is 0.0131239. Benign: BS1 is strong because the African/African American gnomAD v4.1 allele frequency is 0.0131239 with 935 variant alleles. Benign: BS2 is supporting because gnomAD v4.1 reports six homozygous observations without clinical information.

BA1 + BS1 + BS2 → Benign

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.

Gene diagram · NM_177438.3 · variants mapped to exon structure

DICER1 NM_177438.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 12 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Met: gnomAD v4.1 African/African American AF 0.0131239 exceeds the DICER1 VCEP BA1 threshold of >0.003 with 935/71,244 alleles.

ClinGen DICER1 VCEP version 1.4 specifies BA1 as frequency >0.003 in a gnomAD subpopulation with >2,000 alleles tested and at least 5 alleles present, and directs users to use the most recent/most comprehensive gnomAD version.gnomAD v4.1 reports AF 0.0131239 in the African/African American subpopulation, corresponding to 935 of 71,244 alleles and 3 homozygotes; this exceeds the VCEP BA1 threshold and satisfies the subpopulation sample requirements.

cspec ↗gnomad_v4 ↗

BS1 strong Benign

Met, strong: gnomAD v4.1 African/African American AF 0.0131239 exceeds the DICER1 VCEP BS1 threshold of >0.0003 with 935/71,244 alleles.

ClinGen DICER1 VCEP version 1.4 specifies BS1 as frequency >0.0003 in a gnomAD subpopulation; the subpopulation must have >2,000 alleles tested and at least 5 alleles present.gnomAD v4.1 reports AF 0.0131239 in the African/African American subpopulation, corresponding to 935 of 71,244 alleles and 3 homozygotes; this exceeds the VCEP BS1 threshold and satisfies the subpopulation sample requirements.

cspec ↗gnomad_v4 ↗

BS2 supporting Benign

Met, supporting: gnomAD v4.1 reports 6 homozygotes, meeting the DICER1 VCEP requirement of at least 2 homozygous observations without clinical information.

ClinGen DICER1 VCEP version 1.4 specifies BS2 Supporting for 2 or more observations of homozygosity in individuals lacking clinical information; Strong requires either 2 or more homozygous observations in healthy individuals or confirmed parental testing, or the specified tumor-free female cohorts.gnomAD v4.1 reports total_hom 6 for the variant, including 3 homozygotes in the African/African American subpopulation; this meets the VCEP's minimum count for the Supporting homozygosity rule, while no clinical health status or parental confirmation is provided.

cspec ↗gnomad_v4 ↗

Assessed · not applied · 1 not met · 11 not assessed

Pathogenic

PS1 Not assessed: no pathogenic DICER1 VCEP comparator at the same nucleotide or amino-acid change is documented for c.1510-4dupT.

PS2 Not assessed: no documented parental testing or confirmed de novo observation is available to calculate the DICER1 VCEP PS2 point total.

PS3 Not assessed: no variant-specific RNA or cleavage assay with validated controls and quantitative functional result is available for c.1510-4dupT.

PS4 Not assessed: no phenotype-point total or case-control enrichment result is available for NM_177438.3:c.1510-4dup.

PM2 Not met: gnomAD v4.1 overall AF 0.00142555 is far above the DICER1 VCEP PM2 threshold of <0.000005, with 2,181 observed alleles.

PP1 Not assessed: no affected relatives or documented segregation data are available to establish even the minimum 3–4 meioses required for PP1 Supporting.

PP3 Not assessed: SpliceAI max delta 0.016 is below PP3 thresholds, but the DICER1 rule requires concordant MaxEntScan, which is unavailable.

PP4 Not assessed: COSMIC reports 2 somatic occurrences, but no qualifying RNase IIIb second-hit and retention data are provided.

Benign

BS3 Not assessed: no variant-specific RNA or cleavage assay with replication, validated controls, and demonstrated normal function is available for c.1510-4dupT.

BS4 Not assessed: no phenotype-positive genotype-negative relatives or documented non-segregation observation is available for the DICER1 BS4 rule.

BP2 Not assessed: no affected-proband co-occurrence or phase evidence documents the VCEP threshold of one trans observation or three cis/unknown observations.

BP4 Not assessed: SpliceAI max delta 0.016 is below the BP4 threshold, but the DICER1 rule requires concordant MaxEntScan, which is unavailable.

N/A · 13 PVS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00142555; MAF= 0.14255%, 2181/1529938 alleles, homozygotes = 6) and has highest observed frequency in the African/African American population (AF= 0.0131239; MAF= 1.31239%, 935/71244 alleles, homozygotes = 3); grpmax FAF= 0.0124254.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0023053; MAF= 0.23053%, 554/240316 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.0132105; MAF= 1.32105%, 291/22028 alleles, homozygotes = 0); grpmax FAF= 0.0114853.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.14% · 2181 / 1,529,938
6 hom · FAF 1.2%

African/African American 935 / 71,244	1.3% 3 hom
Remaining individuals 153 / 59,082	0.26% 2 hom
Admixed American 81 / 56,472	0.14%
East Asian 55 / 43,228	0.13%
Middle Eastern 7 / 5,796	0.12%
European (Finnish) 64 / 59,642	0.11%
South Asian 80 / 87,348	0.092% 1 hom
European (non-Finnish) 792 / 1,118,074	0.071%
Ashkenazi Jewish 14 / 28,150	0.05%

+ 1 not observed (Amish)

gnomAD v2.1

0.23% · 554 / 240,316
0 hom · FAF 1.1%

African/African American 291 / 22,028	1.3%
East Asian 43 / 16,930	0.25%
Remaining individuals 9 / 5,844	0.15%
Admixed American 41 / 28,314	0.14%
European (Finnish) 25 / 20,010	0.12%
Ashkenazi Jewish 9 / 8,486	0.11%
European (non-Finnish) 113 / 112,748	0.1%
South Asian 23 / 25,956	0.089%

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 220593)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV104413821, n = 2 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 6 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

24761742 ↗ DICER1-Related Tumor Predisposition. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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