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]
Link to SEPIO compliant JSON-LD document

Variant: NM_177438.3(DICER1):c.2516C>T (p.Ser839Phe)

CA129336

30566 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: efaf6fc3-d5c9-4c9e-90d0-aa736abfd98d
Approved on: 2024-01-09
Published on: 2024-01-17

HGVS expressions

NM_177438.3:c.2516C>T
NM_177438.3(DICER1):c.2516C>T (p.Ser839Phe)
NC_000014.9:g.95108014G>A
CM000676.2:g.95108014G>A
NC_000014.8:g.95574351G>A
CM000676.1:g.95574351G>A
NC_000014.7:g.94644104G>A
NG_016311.1:g.54409C>T
ENST00000343455.8:c.2516C>T
ENST00000393063.6:c.2516C>T
ENST00000526495.6:c.2516C>T
ENST00000532939.3:c.2516C>T
ENST00000556045.6:c.2516C>T
ENST00000675540.1:c.338C>T
ENST00000675995.1:c.*832C>T
ENST00000343455.7:c.2516C>T
ENST00000393063.5:c.2516C>T
ENST00000526495.5:c.2516C>T
ENST00000527414.5:c.2516C>T
ENST00000541352.5:c.2516C>T
NM_001195573.1:c.2516C>T
NM_001271282.2:c.2516C>T
NM_001291628.1:c.2516C>T
NM_030621.4:c.2516C>T
NM_177438.2:c.2516C>T
NM_001271282.3:c.2516C>T
NM_001291628.2:c.2516C>T
NM_001395677.1:c.2516C>T
NM_001395678.1:c.2516C>T
NM_001395679.1:c.2516C>T
NM_001395680.1:c.2516C>T
NM_001395682.1:c.2516C>T
NM_001395683.1:c.2516C>T
NM_001395684.1:c.2516C>T
NM_001395685.1:c.2516C>T
NM_001395686.1:c.2234C>T
NM_001395687.1:c.2111C>T
NM_001395688.1:c.2111C>T
NM_001395689.1:c.2111C>T
NM_001395690.1:c.2111C>T
NM_001395691.1:c.1949C>T
NM_001395692.1:c.2516C>T
NM_001395693.1:c.2516C>T
NM_001395694.1:c.2516C>T
NM_001395695.1:c.2516C>T
NM_001395696.1:c.2111C>T
NM_001395697.1:c.833C>T
NR_172715.1:n.2934C>T
NR_172716.1:n.2861C>T
NR_172717.1:n.3028C>T
NR_172718.1:n.3028C>T
NR_172719.1:n.2861C>T
NR_172720.1:n.2861C>T

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PS4_Supporting PS3_Supporting PP1_Moderate PP4
Not Met criteria codes 12
PM1 PM5 BA1 BS2 BS4 BS3 BS1 BP2 BP4 PS2 PS1 PP3

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 1.2.0

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.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID: 37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).
PS4_Supporting
This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). Note: all had thyroid phenotypes
PS3_Supporting
In vitro cleavage assay in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID: 37333613).
PP1_Moderate
The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596).
PP4
At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 27459524, 26033159).
Not Met criteria codes
PM1
This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).
PM5
Another missense variant c.2516C>G (p.Ser839Cys) in the same codon has been reported (ClinVar Variation ID: 935119). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER1 VCEP (PM5 not met).
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 1 unrelated female without tumors through age 50 (BS2 not met; Ambry).
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
BP2
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 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
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
PP3
The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
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