Classification rationale

BA1BS1BS2 Benign

DICER1 c.4680G>A

The DICER1 c.4680G>A (p.Ala1560=) variant has been reported in ClinVar with benign classifications from multiple clinical laboratories.¹ This variant is common in population databases, including gnomAD v4.1 with total allele frequency 0.00631 and African/African American allele frequency 0.11919, which is well above the DICER1 BA1 threshold of 0.003; gnomAD-Canada also shows allele frequency 0.00863 with 11 homozygotes.² Computational data do not support a splice-disrupting effect, with SpliceAI max delta score 0.01, and the REVEL score is 0.07.³

BA1 + BS1 + BS2 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v4 ↗gnomad_canada ↗

3 spliceai ↗revel

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

DICER1 NM_177438.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

Population frequency exceeds the DICER1 BA1 threshold of >0.003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.003 threshold and includes far more than 5 alleles with >2000 alleles tested.

gnomAD v4.1 African/African American AF 0.11919046476281897 (8940/75006)

cspec ↗gnomad_v4 ↗

✓

BS1 strong Benign

Population frequency exceeds the DICER1 BS1 threshold of >0.0003 in a qualifying gnomAD subpopulation. In gnomAD v4.1, the African/African American subpopulation frequency is 0.11919 (8940/75006 alleles), which is far above the 0.0003 threshold.

gnomAD v4.1 African/African American AF 0.11919046476281897 (8940/75006)

cspec ↗gnomad_v4 ↗

✓

BS2 supporting Benign

This variant is observed in homozygous state in population datasets lacking detailed clinical information, which supports BS2 at the supporting level under the DICER1 specification. gnomAD v4.1 reports 596 homozygotes, gnomAD v2.1 reports 195 homozygotes, and gnomAD-Canada reports 11 homozygotes.

gnomAD v4.1 homozygotes 596gnomAD v2.1 homozygotes 195gnomAD-Canada homozygotes 11

cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic same-amino-acid comparator identified for this synonymous change, so PS1 is not supported.

PS2 No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.

PS3 No RNA assay or other DICER1-validated functional assay was identified showing an abnormal effect for this variant, so PS3 is not met.

PS4 No case-level phenotype point data were identified to show enrichment in individuals with DICER1-related disease, so PS4 cannot be applied.

PM2 Population frequency is far above the DICER1 PM2 threshold of <0.000005.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 Available computational evidence does not support a damaging effect.

PP4 No tumor testing evidence was identified showing a qualifying DICER1 hotspot second hit with retention of this germline variant, so PP4 cannot be applied.

Benign

BS3 No RNA study was identified showing no splicing impact for this synonymous variant, so BS3 cannot be applied.

BS4 No segregation data were identified showing the variant absent in phenotype-positive relatives, so BS4 cannot be assessed.

BP2 No co-occurrence or phase data were identified to support BP2.

BP4 Available computational evidence argues against a splice-disrupting effect, with SpliceAI max delta score 0.01 and REVEL 0.07, but the DICER1 specification for synonymous/non-coding BP4 calls for concordance of MaxEntScan and SpliceAI.

BP7 This is a synonymous variant, but the DICER1 BP7 rule requires BP4 and also no evidence that the nucleotide is highly conserved.

N/A · 12 PVS1 · PM1 · PM3 · PM4 · 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= 0.00631039; MAF= 0.63104%, 10186/1614164 alleles, homozygotes = 596) and has highest observed frequency in the African/African American population (AF= 0.11919; MAF= 11.91905%, 8940/75006 alleles, homozygotes = 577); grpmax FAF= 0.117124.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0117076; MAF= 1.17076%, 3311/282808 alleles, homozygotes = 195) and has highest observed frequency in the African/African American population (AF= 0.122266; MAF= 12.22658%, 3052/24962 alleles, homozygotes = 193); grpmax FAF= 0.1183.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00863286; MAF= 0.86329%, 159/18418 alleles, homozygotes = 11) and has highest observed frequency in the afr population (AF= 0.140196; grpmax FAF95= 0.121485).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.63% · 10186 / 1,614,164
596 hom · FAF 12%

African/African American 8940 / 75,006	12% 577 hom
Remaining individuals 529 / 62,512	0.85% 13 hom
Admixed American 454 / 60,030	0.76% 4 hom
Middle Eastern 21 / 6,062	0.35% 1 hom
South Asian 37 / 91,080	0.041% 1 hom
European (non-Finnish) 202 / 1,180,032	0.017%
East Asian 2 / 44,878	0.0045%
European (Finnish) 1 / 64,044	0.0016%

+ 2 not observed (Amish, Ashkenazi Jewish)

gnomAD v2.1

1.2% · 3311 / 282,808
195 hom · FAF 12%

African/African American 3052 / 24,962	12% 193 hom
Admixed American 194 / 35,438	0.55% 2 hom
Remaining individuals 33 / 7,224	0.46%
South Asian 6 / 30,616	0.02%
European (non-Finnish) 24 / 129,132	0.019%
East Asian 2 / 19,948	0.01%

+ 2 not observed (Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

0.86% · 159 / 18,418
11 hom · FAF 12%

African/African American 143 / 1,020	14% 11 hom
Remaining individuals 8 / 1,138	0.7%
Latino/Admixed American 5 / 838	0.6%
European (non-Finnish) 3 / 11,740	0.026%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 261925)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.07.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 · 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

Re-run this variant?