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
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_177438.2(DICER1):c.5107C>T (p.Arg1703Cys)

CA10583187

242130 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c327f58c-9a2c-4267-9b8b-346274bc72c7
Approved on: 2024-08-27
Published on: 2024-09-16

HGVS expressions

NM_177438.2:c.5107C>T
NM_177438.2(DICER1):c.5107C>T (p.Arg1703Cys)
NC_000014.9:g.95094145G>A
CM000676.2:g.95094145G>A
NC_000014.8:g.95560482G>A
CM000676.1:g.95560482G>A
NC_000014.7:g.94630235G>A
NG_016311.1:g.68278C>T
ENST00000529720.2:c.5107C>T
ENST00000531162.7:c.5107C>T
ENST00000674628.2:c.5107C>T
ENST00000675540.2:c.*1757C>T
ENST00000696733.1:c.5107C>T
ENST00000696734.1:c.5107C>T
ENST00000696735.1:n.2094C>T
ENST00000696736.1:c.5107C>T
ENST00000696920.1:n.5370C>T
ENST00000696921.1:n.6213C>T
ENST00000696922.1:n.5516C>T
ENST00000696923.1:c.5107C>T
ENST00000696924.1:c.5107C>T
ENST00000696925.1:n.5516C>T
ENST00000343455.8:c.5107C>T
ENST00000393063.6:c.5107C>T
ENST00000526495.6:c.5107C>T
ENST00000556045.6:c.5107C>T
ENST00000675540.1:c.2852C>T
ENST00000675995.1:c.*3423C>T
ENST00000343455.7:c.5107C>T
ENST00000393063.5:c.5107C>T
ENST00000526495.5:c.5107C>T
ENST00000527414.5:c.5107C>T
ENST00000541352.5:c.5107C>T
ENST00000556045.5:c.1801C>T
NM_001195573.1:c.5107C>T
NM_001271282.2:c.5107C>T
NM_001291628.1:c.5107C>T
NM_030621.4:c.5107C>T
NM_001271282.3:c.5107C>T
NM_001291628.2:c.5107C>T
NM_177438.3:c.5107C>T
NM_001395677.1:c.5107C>T
NM_001395678.1:c.5107C>T
NM_001395679.1:c.5107C>T
NM_001395680.1:c.5107C>T
NM_001395682.1:c.5107C>T
NM_001395683.1:c.5107C>T
NM_001395684.1:c.5107C>T
NM_001395685.1:c.5107C>T
NM_001395686.1:c.4825C>T
NM_001395687.1:c.4702C>T
NM_001395688.1:c.4702C>T
NM_001395689.1:c.4702C>T
NM_001395690.1:c.4702C>T
NM_001395691.1:c.4540C>T
NM_001395697.1:c.3424C>T
NR_172715.1:n.5525C>T
NR_172716.1:n.5709C>T
NR_172717.1:n.5619C>T
NR_172718.1:n.5542C>T
NR_172719.1:n.5375C>T
NR_172720.1:n.5452C>T

Uncertain Significance

Met criteria codes 2
PP3 PM1_Supporting
Not Met criteria codes 15
BS4 BS3 BS1 BS2 BP2 BP4 BA1 PS2 PS4 PS3 PS1 PP4 PP1 PM2 PM5

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
NM_177438.2(DICER1):c.5107C>T variant in DICER1 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1703 (p.Arg1703Cys). The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.916) (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: PM1_Supporting, PP3. (Bayesian Points: 2; VCEP specifications version 1.3.0; 08/27/2024).
Met criteria codes
PP3
In silico tools predict damaging impact of the variant on protein function (REVEL: 0.916) (PP3).
PM1_Supporting
This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Sequencing of RNA from patients showed that this variant does not affect splicing; however, this variant is not intronic or synonymous, so this data does not apply (Internal contributors). Invitae RNA data from 2 samples was negative.
BS1
The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
BS2
This variant has been observed in a homozygous state in 1 individual without clinical information (gnomAD) and has been observed in <10 females tumor-free through age 50 (Internal lab contributors) (BS2 not met).
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
BA1
The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
9 Individuals without DICER1 phenotypes (Invitae, Ambry)
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 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
PM2
The total allele frequency in gnomAD v4.1.0 is 0.000003098 (5/1614132 alleles) with a highest population minor allele frequency of 0.00002196 (2/91074 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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