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.2455T>C (p.Tyr819His)

CA390881994

479637 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0874d224-0c58-4990-a171-08d65b199b65
Approved on: 2025-01-07
Published on: 2025-01-27

HGVS expressions

NM_177438.3:c.2455T>C
NM_177438.3(DICER1):c.2455T>C (p.Tyr819His)
NC_000014.9:g.95108075A>G
CM000676.2:g.95108075A>G
NC_000014.8:g.95574412A>G
CM000676.1:g.95574412A>G
NC_000014.7:g.94644165A>G
NG_016311.1:g.54348T>C
ENST00000529720.2:c.2455T>C
ENST00000531162.7:c.2455T>C
ENST00000674628.2:c.2455T>C
ENST00000675540.2:c.2455T>C
ENST00000696733.1:c.2455T>C
ENST00000696734.1:c.2455T>C
ENST00000696736.1:c.2455T>C
ENST00000696737.1:c.2455T>C
ENST00000696738.1:n.343T>C
ENST00000696920.1:n.2718T>C
ENST00000696921.1:n.3561T>C
ENST00000696922.1:n.2864T>C
ENST00000696923.1:c.2455T>C
ENST00000696924.1:c.2455T>C
ENST00000696925.1:n.2864T>C
ENST00000696927.1:n.2050T>C
ENST00000343455.8:c.2455T>C
ENST00000393063.6:c.2455T>C
ENST00000526495.6:c.2455T>C
ENST00000532939.3:c.2455T>C
ENST00000556045.6:c.2455T>C
ENST00000675540.1:c.277T>C
ENST00000675995.1:c.*771T>C
ENST00000343455.7:c.2455T>C
ENST00000393063.5:c.2455T>C
ENST00000526495.5:c.2455T>C
ENST00000527414.5:c.2455T>C
ENST00000541352.5:c.2455T>C
NM_001195573.1:c.2455T>C
NM_001271282.2:c.2455T>C
NM_001291628.1:c.2455T>C
NM_030621.4:c.2455T>C
NM_177438.2:c.2455T>C
NM_001271282.3:c.2455T>C
NM_001291628.2:c.2455T>C
NM_001395677.1:c.2455T>C
NM_001395678.1:c.2455T>C
NM_001395679.1:c.2455T>C
NM_001395680.1:c.2455T>C
NM_001395682.1:c.2455T>C
NM_001395683.1:c.2455T>C
NM_001395684.1:c.2455T>C
NM_001395685.1:c.2455T>C
NM_001395686.1:c.2173T>C
NM_001395687.1:c.2050T>C
NM_001395688.1:c.2050T>C
NM_001395689.1:c.2050T>C
NM_001395690.1:c.2050T>C
NM_001395691.1:c.1888T>C
NM_001395692.1:c.2455T>C
NM_001395693.1:c.2455T>C
NM_001395694.1:c.2455T>C
NM_001395695.1:c.2455T>C
NM_001395696.1:c.2050T>C
NM_001395697.1:c.772T>C
NR_172715.1:n.2873T>C
NR_172716.1:n.2800T>C
NR_172717.1:n.2967T>C
NR_172718.1:n.2967T>C
NR_172719.1:n.2800T>C
NR_172720.1:n.2800T>C
More

Uncertain Significance

Met criteria codes 2
BS2_Supporting PP3
Not Met criteria codes 16
BS3 BS4 BS1 BP2 BP4 PS4 PS3 PS2 PS1 PP4 PP1 PM6 PM2 PM1 PM5 BA1

Evidence Links 1

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:c.2455T>C variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 819 (p.Tyr819His). 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; PMIDs: 28012864, Internal lab contributors). 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). The total allele frequency in gnomAD v4.1.0 is 0.000006198 (10/1613442 alleles) with a highest population minor allele frequency of 0.000007631 (9/1179402 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.876) (PP3). 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: BS2_supporting, PP3. (Bayesian Points: 0; VCEP specifications version 1.3.0; 01/07/2025)
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).
PP3
In silico tools predict damaging impact of the variant on protein function (REVEL: 0.876) (PP3).
Not Met criteria codes
BS3
Average percentage of 3p and 5p-derived miRNAs analyzed, reported DICER1 mutation did not affect average percentage of 3p and 5p-derived mRNAs by RNA sequencing. VCEP agreed on 1/7/25 that this evidence should NOT be considered. PubMed:28012864
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
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; PMIDs: 28012864, Internal lab contributors).
PS3
Average percentage of 3p and 5p-derived miRNAs analyzed, reported DICER1 mutation did not affect average percentage of 3p and 5p-derived mRNAs by RNA sequencing. VCEP agreed on 1/7/25 that this evidence should NOT be considered. PubMed:28012864
PS2
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 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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
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).
PM5
Two different missense variants, c.2456A>T (p.Tyr819Phe), c.2456A>G (p.Tyr819Cys), in the same codon have been reported (Variation ID: 1354204; Variation ID: 886998). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
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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