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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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