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 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.5470G>C (p.Gly1824Arg)

CA390864581

483420 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 44eb2a19-5311-47f1-b773-eca40b4f2ab6
Approved on: 2025-08-26
Published on: 2025-09-19

HGVS expressions

NM_177438.3:c.5470G>C
NM_177438.3(DICER1):c.5470G>C (p.Gly1824Arg)
NC_000014.9:g.95091260C>G
CM000676.2:g.95091260C>G
NC_000014.8:g.95557597C>G
CM000676.1:g.95557597C>G
NC_000014.7:g.94627350C>G
NG_016311.1:g.71163G>C
ENST00000529720.2:c.5470G>C
ENST00000531162.7:c.5470G>C
ENST00000674628.2:c.5470G>C
ENST00000675540.2:c.*2120G>C
ENST00000696733.1:c.*92G>C
ENST00000696734.1:c.*125G>C
ENST00000696735.1:n.2457G>C
ENST00000696736.1:c.5470G>C
ENST00000696920.1:n.5733G>C
ENST00000696921.1:n.6576G>C
ENST00000696922.1:n.8401G>C
ENST00000696923.1:c.*125G>C
ENST00000696924.1:c.*92G>C
ENST00000696925.1:n.8401G>C
ENST00000343455.8:c.5470G>C
ENST00000393063.6:c.5470G>C
ENST00000526495.6:c.5470G>C
ENST00000556045.6:c.*187G>C
ENST00000675540.1:c.3215G>C
ENST00000675995.1:c.*3786G>C
ENST00000343455.7:c.5470G>C
ENST00000393063.5:c.5470G>C
ENST00000526495.5:c.5470G>C
ENST00000527414.5:c.5470G>C
ENST00000527416.2:n.63G>C
ENST00000527554.2:n.163G>C
ENST00000541352.5:c.5365-151G>C
ENST00000556045.5:c.2164G>C
NM_001195573.1:c.5365-151G>C
NM_001271282.2:c.5470G>C
NM_001291628.1:c.5470G>C
NM_030621.4:c.5470G>C
NM_177438.2:c.5470G>C
NM_001271282.3:c.5470G>C
NM_001291628.2:c.5470G>C
NM_001395677.1:c.5470G>C
NM_001395678.1:c.5470G>C
NM_001395679.1:c.5470G>C
NM_001395680.1:c.5470G>C
NM_001395682.1:c.5470G>C
NM_001395683.1:c.5470G>C
NM_001395684.1:c.5470G>C
NM_001395685.1:c.5470G>C
NM_001395686.1:c.5188G>C
NM_001395687.1:c.5065G>C
NM_001395688.1:c.5065G>C
NM_001395689.1:c.5065G>C
NM_001395690.1:c.5065G>C
NM_001395691.1:c.4903G>C
NM_001395697.1:c.3787G>C
NR_172715.1:n.5888G>C
NR_172716.1:n.6072G>C
NR_172717.1:n.5982G>C
NR_172718.1:n.5905G>C
NR_172719.1:n.5738G>C
NR_172720.1:n.5941G>C
More

Uncertain Significance

Met criteria codes 2
PM2_Supporting PM1_Supporting
Not Met criteria codes 23
PM6 PM5 PM3 PM4 BA1 BS2 BS4 BS1 BP4 BP1 BP2 BP3 BP7 BP5 PVS1 PS3 PS4 PS1 PS2 PP4 PP1 PP3 PP2

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 1.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.2:c.5470G>C variant in DICER1 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1824 (p.Gly1824Arg). Although this variant has been observed in individuals undergoing genetic sequencing, 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 6.195e-7 (1/1614126 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). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 1.4.0; 08/26/2025)
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 6.195e-7 (1/1614126 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).
PM1_Supporting
This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592).
Not Met criteria codes
PM6
This evidence code is not currently applicable for DICER1 VCEP curations.
PM5
3 different missense variants, c.5471G>A (p.Gly1824Glu), c.5471G>T (p.Gly1824Val), c.5470G>C (p.Gly1824Arg), in the same codon have not been classified as pathogenic for DICER1 syndrome by the ClinGen DICER1 VCEP.
PM3
This evidence code is not currently applicable for DICER1 VCEP curations.
PM4
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
BS2
This variant has been seen in 3 unrelated females (Ambry internal data) and 2 unrelated females (Invitae internal data) without tumors through age 50.
BS4
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
BP4
The computational predictor REVEL gives a score of 0.692, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
BP1
This evidence code is not currently applicable for DICER1 VCEP curations.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
This evidence code is not currently applicable for DICER1 VCEP curations.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
This evidence code is not currently applicable for DICER1 VCEP curations.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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 individuals undergoing genetic sequencing, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The computational predictor REVEL gives a score of 0.692, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
PP2
This evidence code is not currently applicable for DICER1 VCEP curations.
Curation History
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