Evidence Repository - Clinical Genome Resources

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.5461A>G (p.Met1821Val)

CA16614591

412149 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6ec0d621-923b-406d-90b2-f1375482dc69

Approved on: 2023-07-10

Published on: 2023-07-20

HGVS expressions

NM_177438.3:c.5461A>G

NM_177438.3(DICER1):c.5461A>G (p.Met1821Val)

NC_000014.9:g.95091269T>C

CM000676.2:g.95091269T>C

NC_000014.8:g.95557606T>C

CM000676.1:g.95557606T>C

NC_000014.7:g.94627359T>C

NG_016311.1:g.71154A>G

ENST00000343455.8:c.5461A>G

ENST00000393063.6:c.5461A>G

ENST00000526495.6:c.5461A>G

ENST00000556045.6:c.*178A>G

ENST00000675540.1:n.3206A>G

ENST00000675995.1:c.*3777A>G

ENST00000343455.7:c.5461A>G

ENST00000393063.5:c.5461A>G

ENST00000526495.5:c.5461A>G

ENST00000527414.5:c.5461A>G

ENST00000527416.2:n.54A>G

ENST00000527554.2:n.154A>G

ENST00000541352.5:c.5365-160A>G

ENST00000556045.5:c.2155A>G

NM_001195573.1:c.5365-160A>G

NM_001271282.2:c.5461A>G

NM_001291628.1:c.5461A>G

NM_030621.4:c.5461A>G

NM_177438.2:c.5461A>G

NM_001271282.3:c.5461A>G

NM_001291628.2:c.5461A>G

NM_001395677.1:c.5461A>G

NM_001395678.1:c.5461A>G

NM_001395679.1:c.5461A>G

NM_001395680.1:c.5461A>G

NM_001395682.1:c.5461A>G

NM_001395683.1:c.5461A>G

NM_001395684.1:c.5461A>G

NM_001395685.1:c.5461A>G

NM_001395686.1:c.5179A>G

NM_001395687.1:c.5056A>G

NM_001395688.1:c.5056A>G

NM_001395689.1:c.5056A>G

NM_001395690.1:c.5056A>G

NM_001395691.1:c.4894A>G

NM_001395697.1:c.3778A>G

NR_172715.1:n.5879A>G

NR_172716.1:n.6063A>G

NR_172717.1:n.5973A>G

NR_172718.1:n.5896A>G

NR_172719.1:n.5729A>G

NR_172720.1:n.5932A>G

Uncertain Significance

PM1_Supporting PM2_Supporting

PM6 PM3 PM5 PM4 BA1 BS4 BS3 BS1 PVS1 BS2 PS4 PS3 PS1 PS2 BP5 BP7 BP2 BP3 BP4 BP1 PP4 PP1 PP3 PP2

Evidence Links 0

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

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.5461A>G variant in DICER1 is a missense variant predicted to cause substitution of methionine by valine at amino acid 1821 (p.Met1821Val). This variant has an allele frequency of 0.000004 (1/236,934 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). The computational predictor REVEL gives a score of 0.54, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 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). 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: PM1_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 1.2.0; 07/10/2023)

PM1_Supporting

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).

PM2_Supporting

This variant has an allele frequency of 0.000004 (1/236,934 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).

PM6

This evidence code is not currently applicable for DICER1 VCEP curations.

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

Another missense variants, c.5461A>C (p.Met1821Leu), in the same codon has not been classified as pathogenic for DICER1 syndrome by the ClinGen DICER1 VCEP.

PM4

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 v2.1.1 is 0.00003 (1/34,260 alleles) in the Latino population, which is less than the ClinGen DICER1 VCEP threshold (>0.003) for BA1 (BA1 not met).

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

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS2

This variant has been seen in 2 unrelated females (Invitae internal data) and 5 unrelated females (Ambry internal data) without tumors through age 50.

PS4

This variant received a total of 0 phenotype points across 7 unrelated probands (Invitae internal data) and 0 phenotype points across 10 unrelated probands. (PS4 not met; Ambry internal data).

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

PS2

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.

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

BP3

This evidence code is not currently applicable for DICER1 VCEP curations.

BP4

The computational predictor REVEL gives a score of 0.54, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).

BP1

This evidence code is not currently applicable for DICER1 VCEP curations.

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

The computational predictor REVEL gives a score of 0.54, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met).

PP2

This evidence code is not currently applicable for DICER1 VCEP curations.

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