Classification rationale

BA1BS1BS2 Benign

DICER1 c.4206+9del unknown · exon 22i

BA1 (stand-alone benign): gnomAD v4.1 allele frequency 35.2% overall and 48.6% in East Asians far exceeds the >0.3% BA1 threshold. BS1 (strong): the same gnomAD frequency far exceeds the >0.03% BS1 threshold, incompatible with a rare tumor-predisposition allele. BS2 (supporting): 7,262 homozygous carriers in gnomAD far exceed the two-observation BS2 threshold. Combined, BA1 (-8) + BS1 (-4) + BS2 (-1) = -13 points, classifying this variant as Benign under the DICER1 VCEP framework.

BA1 + BS1 + BS2 → Benign

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

DICER1 NM_177438.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 15 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 (stand-alone benign): gnomAD v4.1 allele frequency 35.2% overall and 48.6% in East Asians far exceeds the >0.3% BA1 threshold.

The DICER1 VCEP Version 1.4 rule states: frequency >0.003 (0.3%) in gnomAD subpopulations; subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.The VCEP clarification states that, in general, the most recent/most comprehensive gnomAD version should be used.gnomAD v4.1 reports AF 0.352171 overall from 207,044/587,908 alleles, 7,262 homozygotes, and East Asian AF 0.485669 from 5,524/11,374 alleles with 132 homozygotes.

cspec ↗gnomad_v4 ↗

BS1 strong Benign

Met (strong): gnomAD allele frequency 35.2% far exceeds the >0.03% BS1 threshold, incompatible with a rare disease-causing allele.

The DICER1 VCEP Version 1.4 rule states: frequency >0.0003 (0.03%) in gnomAD subpopulations; subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.gnomAD v4.1 reports overall AF 0.352171 (207,044/587,908 alleles) and East Asian AF 0.485669 (5,524/11,374 alleles), with 7,262 overall homozygotes and 132 East Asian homozygotes.

cspec ↗gnomad_v4 ↗

BS2 supporting Benign

Met (supporting): 7,262 homozygous carriers in gnomAD far exceed the two-observation BS2 threshold.

The DICER1 VCEP Version 1.4 BS2 Supporting rule permits 2 or more observations of homozygosity in individuals lacking clinical information.gnomAD v4.1 reports 7,262 homozygotes overall and 132 homozygotes in the East Asian subpopulation; these population records do not provide individual-level phenotype or parental-testing information in the case bundle.

cspec ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PVS1 Not met: intronic +9 deletion is outside canonical splice sites, with no RNA evidence of aberrant splicing or truncation.

PS1 Not assessed: no pathogenic ClinGen DICER1 comparator at the same nucleotide was available to establish an equal-or-worse splice impact.

PS2 Not assessed: no documented de novo occurrence with parental testing or confirmed maternity and paternity was available.

PS3 Not assessed: no variant-specific RNA or cleavage assay was available; computational SpliceAI alone cannot meet PS3.

PS4 Not met: gnomAD allele frequency 35.2% makes a pathogenic population effect implausible, and PS4 is excluded when BA1/BS1 are met.

PM2 Not met: gnomAD allele frequency 35.2% vastly exceeds the <0.0005% PM2 rarity threshold.

PM4 Not met: no in-frame protein change or stop-loss is demonstrated for this intronic deletion.

PP1 Not assessed: no variant-carrying affected relatives or informative meioses were documented.

PP3 Not assessed: MaxEntScan data were unavailable, so the required SpliceAI/MaxEntScan concordance could not be established.

PP4 Not assessed: no paired tumor findings (somatic RNase IIIb hotspot second hit) were available for the PP4 tumor rule.

Benign

BS3 Not assessed: no benign functional assay (RNA or cleavage) was available for this variant.

BS4 Not assessed: no family genotypes or documented non-segregation were available.

BP2 Not assessed: no family, phase, or co-occurring pathogenic DICER1 variant observations were available.

BP4 Not assessed: MaxEntScan data were unavailable, so the required SpliceAI/MaxEntScan concordance could not be established.

BP7 Not assessed: BP7 requires BP4 to be met, but BP4 could not be assessed without MaxEntScan data.

N/A · 10 PM1 · PM3 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.352171; MAF= 35.21707%, 207044/587908 alleles, homozygotes = 7262) and has highest observed frequency in the East Asian population (AF= 0.485669; MAF= 48.56691%, 5524/11374 alleles, homozygotes = 132); grpmax FAF= 0.476004.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0327049; MAF= 3.27049%, 7782/237946 alleles, homozygotes = 1125) and has highest observed frequency in the African/African American population (AF= 0.151915; MAF= 15.19154%, 3117/20518 alleles, homozygotes = 543); grpmax FAF= 0.314123.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.46475563909774437, 2967/6384 alleles, homozygotes = 279).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

35% · 207044 / 587,908
7262 hom · FAF 48%

East Asian 5524 / 11,374	49% 132 hom
Admixed American 11239 / 23,246	48% 871 hom
African/African American 21229 / 44,666	48% 2469 hom
South Asian 15875 / 35,160	45% 738 hom
Amish 96 / 224	43% 2 hom
European (Finnish) 6981 / 18,108	39% 325 hom
Remaining individuals 8259 / 22,654	36% 214 hom
Ashkenazi Jewish 3230 / 9,070	36% 87 hom
Middle Eastern 748 / 2,204	34% 30 hom
European (non-Finnish) 133863 / 421,202	32% 2394 hom

gnomAD v2.1

3.3% · 7782 / 237,946
1125 hom · FAF 31%

African/African American 3117 / 20,518	15% 543 hom
European (Finnish) 595 / 18,426	3.2% 55 hom
Remaining individuals 190 / 6,276	3% 15 hom
European (non-Finnish) 2811 / 110,542	2.5% 297 hom
East Asian 317 / 17,502	1.8% 43 hom
Admixed American 437 / 29,630	1.5% 95 hom
Ashkenazi Jewish 86 / 9,046	0.95% 16 hom
South Asian 229 / 26,006	0.88% 61 hom

gnomAD Canada 🇨🇦

46% · 2967 / 6,384
279 hom · FAF 49%

⚠ LCR indel · split

South Asian 336 / 630	53% 40 hom
East Asian 246 / 464	53% 15 hom
African/African American 370 / 720	51% 61 hom
Latino/Admixed American 188 / 374	50% 17 hom
European (non-Finnish) 1542 / 3,494	44% 122 hom
Remaining individuals 161 / 374	43% 15 hom
Middle Eastern 21 / 52	40% 1 hom
Ashkenazi Jewish 102 / 272	38% 8 hom
European (Finnish) 1 / 4	25%

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 1166424)

ClinVar ↗

In silico

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

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; COSV58618229, n = 7 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 · 5 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

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