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.4874C>A (p.Ser1625Tyr)

CA349727

220773 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
UUID: c55a9e9c-9d61-49e1-93d1-ecabbdec36a2
Approved on: 2024-01-09
Published on: 2024-01-17

HGVS expressions

NM_177438.3:c.4874C>A
NM_177438.3(DICER1):c.4874C>A (p.Ser1625Tyr)
NC_000014.9:g.95096046G>T
CM000676.2:g.95096046G>T
NC_000014.8:g.95562383G>T
CM000676.1:g.95562383G>T
NC_000014.7:g.94632136G>T
NG_016311.1:g.66377C>A
ENST00000343455.8:c.4874C>A
ENST00000393063.6:c.4874C>A
ENST00000526495.6:c.4874C>A
ENST00000532939.3:c.4874C>A
ENST00000556045.6:c.4874C>A
ENST00000675540.1:c.2619C>A
ENST00000675995.1:c.*3190C>A
ENST00000343455.7:c.4874C>A
ENST00000393063.5:c.4874C>A
ENST00000526495.5:c.4874C>A
ENST00000527414.5:c.4874C>A
ENST00000532939.2:c.909C>A
ENST00000541352.5:c.4874C>A
ENST00000556045.5:c.1568C>A
NM_001195573.1:c.4874C>A
NM_001271282.2:c.4874C>A
NM_001291628.1:c.4874C>A
NM_030621.4:c.4874C>A
NM_177438.2:c.4874C>A
NM_001271282.3:c.4874C>A
NM_001291628.2:c.4874C>A
NM_001395677.1:c.4874C>A
NM_001395678.1:c.4874C>A
NM_001395679.1:c.4874C>A
NM_001395680.1:c.4874C>A
NM_001395682.1:c.4874C>A
NM_001395683.1:c.4874C>A
NM_001395684.1:c.4874C>A
NM_001395685.1:c.4874C>A
NM_001395686.1:c.4592C>A
NM_001395687.1:c.4469C>A
NM_001395688.1:c.4469C>A
NM_001395689.1:c.4469C>A
NM_001395690.1:c.4469C>A
NM_001395691.1:c.4307C>A
NM_001395692.1:c.4874C>A
NM_001395693.1:c.4874C>A
NM_001395694.1:c.4874C>A
NM_001395695.1:c.4874C>A
NM_001395696.1:c.4469C>A
NM_001395697.1:c.3191C>A
NR_172715.1:n.5292C>A
NR_172716.1:n.5476C>A
NR_172717.1:n.5386C>A
NR_172718.1:n.5309C>A
NR_172719.1:n.5142C>A
NR_172720.1:n.5219C>A
More

Likely Benign

Met criteria codes 3
BP4 PM2_Supporting BS2_Supporting
Not Met criteria codes 17
PM1 PM5 PM4 PVS1 BA1 BS4 BS3 BS1 BP7 BP2 PS4 PS2 PS3 PS1 PP4 PP1 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.4874C>A variant in DICER1 is a missense variant predicted to cause substitution of serine by tyrosine at amino acid 1625 (p.Ser1625Tyr). 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: 61756). This variant has an allele frequency of 0.000004222 (1/236838 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.128; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, PM2_Supporting, BP4. (Bayesian Points: -1; VCEP specifications version 1.2.0; 01/09/2024)
Met criteria codes
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.128; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
PM2_Supporting
This variant has an allele frequency of 0.000004222 (1/236838 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (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: 61756).
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
3 different missense variants, c.4874C>T (p.Ser1625Phe), c.4874C>G (p.Ser1625Cys), c.4873T>C (p.Ser1625Pro), in the same codon have been reported (ClinVar Variation IDs 477225, 242124, 412053). 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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BP7
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
PS4
This variant received a total of 0 phenotype points across 36 unrelated probands. (PS4 not met; GTR IDs: 26957, 61756, 500031).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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