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]
Link to SEPIO compliant JSON-LD document

Variant: NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)

CA7331526

242032 (ClinVar)

Gene: DICER1
Condition: DICER1-related tumor predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 776daba8-46ba-4339-8fc1-22f854ce32fb

HGVS expressions

NM_177438.3:c.1124C>G
NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)
NC_000014.9:g.95124448G>C
CM000676.2:g.95124448G>C
NC_000014.8:g.95590785G>C
CM000676.1:g.95590785G>C
NC_000014.7:g.94660538G>C
NG_016311.1:g.37975C>G
ENST00000343455.8:c.1124C>G
ENST00000393063.6:c.1124C>G
ENST00000526495.6:c.1124C>G
ENST00000532939.3:c.1124C>G
ENST00000556045.6:c.1124C>G
ENST00000674628.1:c.1124C>G
ENST00000675995.1:c.1124C>G
ENST00000343455.7:c.1124C>G
ENST00000393063.5:c.1124C>G
ENST00000526495.5:c.1124C>G
ENST00000527414.5:c.1124C>G
ENST00000541352.5:c.1124C>G
NM_001195573.1:c.1124C>G
NM_001271282.2:c.1124C>G
NM_001291628.1:c.1124C>G
NM_030621.4:c.1124C>G
NM_177438.2:c.1124C>G
NM_001271282.3:c.1124C>G
NM_001291628.2:c.1124C>G
NM_001395677.1:c.1124C>G
NM_001395678.1:c.1124C>G
NM_001395679.1:c.1124C>G
NM_001395680.1:c.1124C>G
NM_001395682.1:c.1124C>G
NM_001395683.1:c.1124C>G
NM_001395684.1:c.1124C>G
NM_001395685.1:c.1124C>G
NM_001395686.1:c.842C>G
NM_001395687.1:c.719C>G
NM_001395688.1:c.719C>G
NM_001395689.1:c.719C>G
NM_001395690.1:c.719C>G
NM_001395691.1:c.557C>G
NM_001395692.1:c.1124C>G
NM_001395693.1:c.1124C>G
NM_001395694.1:c.1124C>G
NM_001395695.1:c.1124C>G
NM_001395696.1:c.719C>G
NM_001395697.1:c.-445C>G
NM_001395698.1:c.719C>G
NM_001395699.1:c.1124C>G
NM_001395700.1:c.1124C>G
NR_172715.1:n.1338C>G
NR_172716.1:n.1469C>G
NR_172717.1:n.1636C>G
NR_172718.1:n.1636C>G
NR_172719.1:n.1469C>G
NR_172720.1:n.1469C>G

Benign

Met criteria codes 2
BS2 BS1
Not Met criteria codes 19
PM5 PM4 PM1 PM6 PVS1 PM2 BA1 BS3 BP4 BP3 BP2 BP5 BP7 PS1 PS4 PS2 PS3 PP4 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.1124C>G variant in DICER1 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 375 (p.Pro375Arg). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors, PMIDs 29641532, 33630087). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004911 (58/118098 alleles) in the European (non-Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). 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). The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2. (Bayesian Points: -8; VCEP specifications version 1.2.0; 08/22/23).
Met criteria codes
BS2
This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors, PMIDs 29641532, 33630087).
BS1
The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004911 (58/118098 alleles) in the European (non-Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1).
Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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).
PM6
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
PM2
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
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
BP3
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
BP5
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This code does not apply PS4 if variant meets BA1/BS1 criteria: However, this variant has been observed in individuals with cancer in the literature (PMIDs 21266384, 28748527, 28873162, 29474644, 32291395; https://doi.org/10.3390/jmp3010001, https://doi.org/10.1093/narcan/zcad030).
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
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).
Approved on: 2023-08-22
Published on: 2023-09-01
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.