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 ClinVar but not with the Allele Registry data
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  • See Evidence submitted by expert panel for details.

Variant: NM_177438.3(DICER1):c.5524A>G (p.Ile1842Val)

242139 (ClinVar)

Gene: DICER1
Condition: dicer1 syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 51f863e6-de18-415d-8380-cb4f086b6b03
Approved on: 2023-04-25
Published on: 2023-05-12

HGVS expressions

NM_177438.3:c.5524A>G
NM_177438.3(DICER1):c.5524A>G (p.Ile1842Val)

Uncertain Significance

Met criteria codes 3
PP3 PM1_Supporting BS2_Supporting
Not Met criteria codes 9
PS3 PS4 PP2 PM2 PVS1 BA1 BS3 BS1 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
DICER1 and miRNA-Processing Gene VCEP
The NM_177438.3:c.5524A>G variant in DICER1 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 1842 (p.Ile1842Val). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors, GTR Lab ID: 50003). The highest population minor allele frequency in gnomAD v 2.1.1 is 0.000034 (4/118,096 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PP3, PM1_Supporting, BS2_Supporting (Bayesian Points: 1; VCEP specifications version 1.1.0; 04/25/2023).
Met criteria codes
PP3
The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3).
PM1_Supporting
This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functional as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592).
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; Internal lab contributors, GTR Lab ID: 50003).
Not Met criteria codes
PS3
RNA data shows leaky results with allele skewing present. Additionally, some of the variant alleles are splicing normally. Normal ~75%; Abnormal ~25% (Internal lab contributor: Ambry)
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v 2.1.1 is 0.000034 (4/118,096 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
The highest population minor allele frequency in gnomAD v 2.1.1 is 0.000034 (4/118,096 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BS3
RNA data shows leaky results with allele skewing present. Additionally, some of the variant alleles are splicing normally. Normal ~75%; Abnormal ~25% (Internal lab contributor: Ambry)
BS1
The highest population minor allele frequency in gnomAD v 2.1.1 is 0.000034 (4/118,096 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met).
BP4
The computational predictor REVEL gives a score of 0.448, which is below the threshold of 0.5, evidence that does not predict a damaging effect on DICER1 function (BP4 is not met).
Curation History
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