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]

Variant: NM_177438.3(DICER1):c.5257G>A (p.Asp1753Asn)

CA390865107

477251 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 680489f0-e62b-4b29-93c1-802471ac2032
Approved on: 2023-08-22
Published on: 2023-09-01

HGVS expressions

NM_177438.3:c.5257G>A
NM_177438.3(DICER1):c.5257G>A (p.Asp1753Asn)
NC_000014.9:g.95093995C>T
CM000676.2:g.95093995C>T
NC_000014.8:g.95560332C>T
CM000676.1:g.95560332C>T
NC_000014.7:g.94630085C>T
NG_016311.1:g.68428G>A
ENST00000343455.8:c.5257G>A
ENST00000393063.6:c.5257G>A
ENST00000526495.6:c.5257G>A
ENST00000556045.6:c.5257G>A
ENST00000675540.1:c.3002G>A
ENST00000675995.1:c.*3573G>A
ENST00000343455.7:c.5257G>A
ENST00000393063.5:c.5257G>A
ENST00000526495.5:c.5257G>A
ENST00000527414.5:c.5257G>A
ENST00000541352.5:c.5257G>A
ENST00000556045.5:c.1951G>A
NM_001195573.1:c.5257G>A
NM_001271282.2:c.5257G>A
NM_001291628.1:c.5257G>A
NM_030621.4:c.5257G>A
NM_177438.2:c.5257G>A
NM_001271282.3:c.5257G>A
NM_001291628.2:c.5257G>A
NM_001395677.1:c.5257G>A
NM_001395678.1:c.5257G>A
NM_001395679.1:c.5257G>A
NM_001395680.1:c.5257G>A
NM_001395682.1:c.5257G>A
NM_001395683.1:c.5257G>A
NM_001395684.1:c.5257G>A
NM_001395685.1:c.5257G>A
NM_001395686.1:c.4975G>A
NM_001395687.1:c.4852G>A
NM_001395688.1:c.4852G>A
NM_001395689.1:c.4852G>A
NM_001395690.1:c.4852G>A
NM_001395691.1:c.4690G>A
NM_001395697.1:c.3574G>A
NR_172715.1:n.5675G>A
NR_172716.1:n.5859G>A
NR_172717.1:n.5769G>A
NR_172718.1:n.5692G>A
NR_172719.1:n.5525G>A
NR_172720.1:n.5602G>A
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Uncertain Significance

Met criteria codes 4
PM1_Supporting BP4 PM2_Supporting BS2_Supporting
Not Met criteria codes 22
BS4 BS3 BS1 BP3 BP2 BP1 BP7 BP5 BA1 PVS1 PS1 PS4 PS3 PS2 PP4 PP1 PP3 PP2 PM5 PM4 PM3 PM6

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.5257G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1753 (p.Asp1753Asn). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; MaxEntScan and SpliceAI: no effect on splicing (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (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; GTR ID: 500031, 61756). 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: PM2_Supporting, BP4, PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.2.0; 08/22/23)
Met criteria codes
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).
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).
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; GTR ID: 500031, 61756).
Not Met criteria codes
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
This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).
BP3
This evidence code is not currently applicable for DICER1 VCEP curations.
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
This evidence code is not currently applicable for DICER1 VCEP curations.
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
This evidence code is not currently applicable for DICER1 VCEP curations.
BA1
This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting).
PVS1
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
PS4
This variant received a total of 0 phenotype points across across 45 unrelated probands. (PS4 not met; GTR ID: 61756, 500031).
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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
PP3
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
PP2
This evidence code is not currently applicable for DICER1 VCEP curations.
PM5
4 different missense variants, c.5259C>G (p.Asp1753Glu), c.5258A>G (p.Asp1753Gly), c.5257G>C (p.Asp1753His), c.5257G>T (p.Asp1753Tyr), in the same codon have been reported (ClinVar Variation IDs: 477252, 1403116, 847357, 659346). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
This evidence code is not currently applicable for DICER1 VCEP curations.
PM6
This evidence code is not currently applicable for DICER1 VCEP curations.
Curation History
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