Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: DICER1 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_177438.3(DICER1):c.5761A>C (p.Asn1921His)

CA7330596

644129 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 031bf5cc-7f84-4513-80aa-81dcbc378402
Approved on: 2025-02-25
Published on: 2025-06-04

HGVS expressions

NM_177438.3:c.5761A>C
NM_177438.3(DICER1):c.5761A>C (p.Asn1921His)
NC_000014.9:g.95090506T>G
CM000676.2:g.95090506T>G
NC_000014.8:g.95556843T>G
CM000676.1:g.95556843T>G
NC_000014.7:g.94626596T>G
NG_016311.1:g.71917A>C
ENST00000529720.2:c.5761A>C
ENST00000531162.7:c.5761A>C
ENST00000674628.2:c.5761A>C
ENST00000675540.2:c.*2411A>C
ENST00000696733.1:c.*383A>C
ENST00000696734.1:c.*416A>C
ENST00000696735.1:n.2748A>C
ENST00000696920.1:n.6024A>C
ENST00000696921.1:n.6867A>C
ENST00000696922.1:n.8692A>C
ENST00000696923.1:c.*416A>C
ENST00000696924.1:c.*383A>C
ENST00000696925.1:n.9062A>C
ENST00000343455.8:c.5761A>C
ENST00000393063.6:c.5761A>C
ENST00000526495.6:c.5761A>C
ENST00000556045.6:c.*478A>C
ENST00000675540.1:c.3506A>C
ENST00000675995.1:c.*4077A>C
ENST00000343455.7:c.5761A>C
ENST00000393063.5:c.5761A>C
ENST00000526495.5:c.5761A>C
ENST00000527414.5:c.5761A>C
ENST00000527416.2:n.347+7A>C
ENST00000541352.5:c.*108A>C
ENST00000556045.5:c.2455A>C
NM_001195573.1:c.*108A>C
NM_001271282.2:c.5761A>C
NM_001291628.1:c.5761A>C
NM_030621.4:c.5761A>C
NM_177438.2:c.5761A>C
NM_001271282.3:c.5761A>C
NM_001291628.2:c.5761A>C
NM_001395677.1:c.5761A>C
NM_001395678.1:c.5761A>C
NM_001395679.1:c.5761A>C
NM_001395680.1:c.5761A>C
NM_001395682.1:c.5761A>C
NM_001395683.1:c.5761A>C
NM_001395684.1:c.5761A>C
NM_001395685.1:c.*307A>C
NM_001395686.1:c.5479A>C
NM_001395687.1:c.5356A>C
NM_001395688.1:c.5356A>C
NM_001395689.1:c.5356A>C
NM_001395690.1:c.5356A>C
NM_001395691.1:c.5194A>C
NM_001395697.1:c.4078A>C
NR_172715.1:n.6172+7A>C
NR_172716.1:n.6363A>C
NR_172717.1:n.6266+7A>C
NR_172718.1:n.6196A>C
NR_172719.1:n.6029A>C
NR_172720.1:n.6232A>C
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Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting
Not Met criteria codes 20
PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM6 PM1 PM4 PM5 PVS1 BS4 BS3 BS1 BS2 BP7 BP2 BP3 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.3(DICER1):c.5761A>C variant in DICER1 is a missense variant predicted to cause substitution of asparagine by histidine at amino acid 1921 (p.Asn1921His). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.0000006196 (1/1613836 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.152; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.3.0; 02/25/2025).
Met criteria codes
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.152; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
PM2_Supporting
This variant has an allele frequency of 0.0000006196 (1/1613836 alleles) across gnomAD v4.1.0 with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors).
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No observations in individuals with phenotypes meeting PP4
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL score = 0.152, no predicted splicing impact per Max Ent Scan or SpliceAI
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
This variant does not reside within a region of the RNAse IIIb domain that is defined as a critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Not observed in 10+ unrelated females from a single source are tumor-free through age 50 and/or in in 2 homozygous individuals without clinical information
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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