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.2051T>C (p.Met684Thr)

CA390883127

479642 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e31f1bdb-5ee0-4637-9ca0-156c92a1d3b7
Approved on: 2025-01-07
Published on: 2025-01-27

HGVS expressions

NM_177438.3:c.2051T>C
NM_177438.3(DICER1):c.2051T>C (p.Met684Thr)
NC_000014.9:g.95112237A>G
CM000676.2:g.95112237A>G
NC_000014.8:g.95578574A>G
CM000676.1:g.95578574A>G
NC_000014.7:g.94648327A>G
NG_016311.1:g.50186T>C
ENST00000529720.2:c.2051T>C
ENST00000531162.7:c.2051T>C
ENST00000674628.2:c.2051T>C
ENST00000675540.2:c.2051T>C
ENST00000696733.1:c.2051T>C
ENST00000696734.1:c.2051T>C
ENST00000696736.1:c.2051T>C
ENST00000696737.1:c.2051T>C
ENST00000696920.1:n.2314T>C
ENST00000696921.1:n.3157T>C
ENST00000696922.1:n.2460T>C
ENST00000696923.1:c.2051T>C
ENST00000696924.1:c.2051T>C
ENST00000696925.1:n.2460T>C
ENST00000696927.1:n.1646T>C
ENST00000696928.1:n.2248T>C
ENST00000343455.8:c.2051T>C
ENST00000393063.6:c.2051T>C
ENST00000526495.6:c.2051T>C
ENST00000532939.3:c.2051T>C
ENST00000556045.6:c.2051T>C
ENST00000675995.1:c.*367T>C
ENST00000343455.7:c.2051T>C
ENST00000393063.5:c.2051T>C
ENST00000526495.5:c.2051T>C
ENST00000527414.5:c.2051T>C
ENST00000541352.5:c.2051T>C
NM_001195573.1:c.2051T>C
NM_001271282.2:c.2051T>C
NM_001291628.1:c.2051T>C
NM_030621.4:c.2051T>C
NM_177438.2:c.2051T>C
NM_001271282.3:c.2051T>C
NM_001291628.2:c.2051T>C
NM_001395677.1:c.2051T>C
NM_001395678.1:c.2051T>C
NM_001395679.1:c.2051T>C
NM_001395680.1:c.2051T>C
NM_001395682.1:c.2051T>C
NM_001395683.1:c.2051T>C
NM_001395684.1:c.2051T>C
NM_001395685.1:c.2051T>C
NM_001395686.1:c.1769T>C
NM_001395687.1:c.1646T>C
NM_001395688.1:c.1646T>C
NM_001395689.1:c.1646T>C
NM_001395690.1:c.1646T>C
NM_001395691.1:c.1484T>C
NM_001395692.1:c.2051T>C
NM_001395693.1:c.2051T>C
NM_001395694.1:c.2051T>C
NM_001395695.1:c.2051T>C
NM_001395696.1:c.1646T>C
NM_001395697.1:c.368T>C
NM_001395698.1:c.1646T>C
NR_172715.1:n.2469T>C
NR_172716.1:n.2396T>C
NR_172717.1:n.2563T>C
NR_172718.1:n.2563T>C
NR_172719.1:n.2396T>C
NR_172720.1:n.2396T>C
More

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 19
PP1 PP3 PP4 PVS1 BS2 BS1 BS4 BS3 BP2 BP7 BA1 PM1 PM5 PM4 PM2 PS1 PS2 PS3 PS4

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_177438.3:c.2051T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 684 (p.Met684Thr). 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; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000001863 (3/1609982 alleles) with a highest population minor allele frequency of 0.00002672 (2/74840 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.345; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025)
Met criteria codes
BP4
In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.345; MaxEntScan and SpliceAI: no effect on splicing) (BP4).
Not Met criteria codes
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
PP4
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
BS2
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
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
BP2
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
4 different missense variants, c.2052G>A (p.Met684Ile), c.2051T>G (p.Met684Arg), c.2050A>T (p.Met684Leu), c.2050A>G (p.Met684Val), in the same codon have been reported (ClinVar Variation IDs: 1785093, 1428490, 820591, 573077). 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
PM2
The total allele frequency in gnomAD v4.1.0 is 0.000001863 (3/1609982 alleles) with a highest population minor allele frequency of 0.00002672 (2/74840 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met).
PS1
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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; Internal lab contributors).
Curation History
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