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.5504A>C (p.Tyr1835Ser)

CA7330659

479625 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8ef563b1-bd4c-4eb9-a0e6-83817f33d2af
Approved on: 2025-06-24
Published on: 2025-07-08

HGVS expressions

NM_177438.3:c.5504A>C
NM_177438.3(DICER1):c.5504A>C (p.Tyr1835Ser)
NC_000014.9:g.95091226T>G
CM000676.2:g.95091226T>G
NC_000014.8:g.95557563T>G
CM000676.1:g.95557563T>G
NC_000014.7:g.94627316T>G
NG_016311.1:g.71197A>C
ENST00000529720.2:c.5504A>C
ENST00000531162.7:c.5504A>C
ENST00000674628.2:c.5504A>C
ENST00000675540.2:c.*2154A>C
ENST00000696733.1:c.*126A>C
ENST00000696734.1:c.*159A>C
ENST00000696735.1:n.2491A>C
ENST00000696736.1:c.5504A>C
ENST00000696920.1:n.5767A>C
ENST00000696921.1:n.6610A>C
ENST00000696922.1:n.8435A>C
ENST00000696923.1:c.*159A>C
ENST00000696924.1:c.*126A>C
ENST00000696925.1:n.8435A>C
ENST00000343455.8:c.5504A>C
ENST00000393063.6:c.5504A>C
ENST00000526495.6:c.5504A>C
ENST00000556045.6:c.*221A>C
ENST00000675540.1:c.3249A>C
ENST00000675995.1:c.*3820A>C
ENST00000343455.7:c.5504A>C
ENST00000393063.5:c.5504A>C
ENST00000526495.5:c.5504A>C
ENST00000527414.5:c.5504A>C
ENST00000527416.2:n.97A>C
ENST00000527554.2:n.197A>C
ENST00000541352.5:c.5365-117A>C
ENST00000556045.5:c.2198A>C
NM_001195573.1:c.5365-117A>C
NM_001271282.2:c.5504A>C
NM_001291628.1:c.5504A>C
NM_030621.4:c.5504A>C
NM_177438.2:c.5504A>C
NM_001271282.3:c.5504A>C
NM_001291628.2:c.5504A>C
NM_001395677.1:c.5504A>C
NM_001395678.1:c.5504A>C
NM_001395679.1:c.5504A>C
NM_001395680.1:c.5504A>C
NM_001395682.1:c.5504A>C
NM_001395683.1:c.5504A>C
NM_001395684.1:c.5504A>C
NM_001395685.1:c.5504A>C
NM_001395686.1:c.5222A>C
NM_001395687.1:c.5099A>C
NM_001395688.1:c.5099A>C
NM_001395689.1:c.5099A>C
NM_001395690.1:c.5099A>C
NM_001395691.1:c.4937A>C
NM_001395697.1:c.3821A>C
NR_172715.1:n.5922A>C
NR_172716.1:n.6106A>C
NR_172717.1:n.6016A>C
NR_172718.1:n.5939A>C
NR_172719.1:n.5772A>C
NR_172720.1:n.5975A>C
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Uncertain Significance

Met criteria codes 2
BS2_Supporting PM1_Supporting
Not Met criteria codes 14
BP2 BP4 PS2 PS4 PS3 PS1 PP1 PM5 PM6 PM2 BA1 BS4 BS3 BS1

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_177438.2:c.5504A>C variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 1835 (p.Tyr1835Ser). The total allele frequency in gnomAD v4.1.0 is 0.000008054 (13/1614058 alleles) with a highest population minor allele frequency of 0.00001102 (13/1180030 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.676, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors, GTR Lab ID: 50003). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.3.0; 06/24/2025).
Met criteria codes
BS2_Supporting
This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors, GTR Lab ID: 50003).
PM1_Supporting
This variant resides within the RNase IIIb domain (PM1_Supporting; PMID: 31342592).
Not Met criteria codes
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL score 0.676; no splicing effects predicted by SpliceAI and varSEAK
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
PS1
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The total allele frequency in gnomAD v4.1.0 is 0.000008054 (13/1614058 alleles) with a highest population minor allele frequency of 0.00001102 (13/1180030 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BA1
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
Internal data from Foulkes lab: Luciferase assay shows downregulation of 3p (mir-25) and 5p sensors (let-7a, let-7c and mir-20a), indicating proper production of the mature miRNA. However, this assay is not an in vitro cleavage assay, as per DICER1 specifications, and thus BS3 is not met.
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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