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.1904A>G (p.Asn635Ser)

CA7331374

479636 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e91d9267-aede-4514-ba57-8eb86a59b69b
Approved on: 2025-01-07
Published on: 2025-01-27

HGVS expressions

NM_177438.3:c.1904A>G
NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser)
NC_000014.9:g.95115670T>C
CM000676.2:g.95115670T>C
NC_000014.8:g.95582007T>C
CM000676.1:g.95582007T>C
NC_000014.7:g.94651760T>C
NG_016311.1:g.46753A>G
ENST00000529720.2:c.1904A>G
ENST00000531162.7:c.1904A>G
ENST00000674628.2:c.1904A>G
ENST00000675540.2:c.1904A>G
ENST00000696733.1:c.1904A>G
ENST00000696734.1:c.1904A>G
ENST00000696736.1:c.1904A>G
ENST00000696737.1:c.1904A>G
ENST00000696920.1:n.2167A>G
ENST00000696921.1:n.3010A>G
ENST00000696922.1:n.2313A>G
ENST00000696923.1:c.1904A>G
ENST00000696924.1:c.1904A>G
ENST00000696925.1:n.2313A>G
ENST00000696927.1:n.1499A>G
ENST00000696928.1:n.2101A>G
ENST00000343455.8:c.1904A>G
ENST00000393063.6:c.1904A>G
ENST00000526495.6:c.1904A>G
ENST00000532939.3:c.1904A>G
ENST00000556045.6:c.1904A>G
ENST00000675995.1:c.*220A>G
ENST00000343455.7:c.1904A>G
ENST00000393063.5:c.1904A>G
ENST00000526495.5:c.1904A>G
ENST00000527414.5:c.1904A>G
ENST00000532458.1:n.493A>G
ENST00000541352.5:c.1904A>G
NM_001195573.1:c.1904A>G
NM_001271282.2:c.1904A>G
NM_001291628.1:c.1904A>G
NM_030621.4:c.1904A>G
NM_177438.2:c.1904A>G
NM_001271282.3:c.1904A>G
NM_001291628.2:c.1904A>G
NM_001395677.1:c.1904A>G
NM_001395678.1:c.1904A>G
NM_001395679.1:c.1904A>G
NM_001395680.1:c.1904A>G
NM_001395682.1:c.1904A>G
NM_001395683.1:c.1904A>G
NM_001395684.1:c.1904A>G
NM_001395685.1:c.1904A>G
NM_001395686.1:c.1622A>G
NM_001395687.1:c.1499A>G
NM_001395688.1:c.1499A>G
NM_001395689.1:c.1499A>G
NM_001395690.1:c.1499A>G
NM_001395691.1:c.1337A>G
NM_001395692.1:c.1904A>G
NM_001395693.1:c.1904A>G
NM_001395694.1:c.1904A>G
NM_001395695.1:c.1904A>G
NM_001395696.1:c.1499A>G
NM_001395697.1:c.221A>G
NM_001395698.1:c.1499A>G
NR_172715.1:n.2322A>G
NR_172716.1:n.2249A>G
NR_172717.1:n.2416A>G
NR_172718.1:n.2416A>G
NR_172719.1:n.2249A>G
NR_172720.1:n.2249A>G
More

Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 17
PM2 PM1 PM5 BS4 BS3 BS1 BS2 BP7 BP2 BP4 PS2 PS4 PS3 PS1 BA1 PP4 PP1

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.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by serine at amino acid 635 (p.Asp635Ser). 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: 33718253, Internal lab contributors). The highest population minor allele frequency in gnomAD v4.1.0 (non-cancer) is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.398), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (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: PP3. (Bayesian Points: 1; VCEP specifications version 1.3.0; 01/07/2025)
Met criteria codes
PP3
While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.398), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). SpliceAI Donor Gain = 0.84 (no loss of native donor) MaxEntScan native donor = 7.37, 7.37; new donor = 0, 4.29
Not Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
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
None observed
BS4
No segregation info
BS3
No experimental data found
BS1
The highest population minor allele frequency in gnomAD v4.1.0 (non-cancer) is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
Missense variant
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
While in silico tools do not predict damaging impact of the variant on protein function (REVEL: 0.398), the splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). SpliceAI Donor Gain = 0.84 (no loss of native donor) MaxEntScan native donor = 7.37, 7.37; new donor = 0, 4.29
PS2
No info
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: 33718253, Internal lab contributors).
PS3
No experimental data found
PS1
None observed
BA1
The highest population minor allele frequency in gnomAD v4.1.0 (non-cancer) is 0.00001 (1/91082 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No segregation info
Curation History
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