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.5038A>G (p.Lys1680Glu)

CA16614163

412143 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ac316871-0fda-40ac-9595-1761ac9278b6

Approved on: 2024-02-27

Published on: 2024-05-08

HGVS expressions

NM_177438.3:c.5038A>G

NM_177438.3(DICER1):c.5038A>G (p.Lys1680Glu)

NC_000014.9:g.95095882T>C

CM000676.2:g.95095882T>C

NC_000014.8:g.95562219T>C

CM000676.1:g.95562219T>C

NC_000014.7:g.94631972T>C

NG_016311.1:g.66541A>G

ENST00000529720.2:c.5038A>G

ENST00000531162.7:c.5038A>G

ENST00000674628.2:c.5038A>G

ENST00000675540.2:c.*1688A>G

ENST00000696733.1:c.5038A>G

ENST00000696734.1:c.5038A>G

ENST00000696735.1:n.2025A>G

ENST00000696736.1:c.5038A>G

ENST00000696737.1:c.5038A>G

ENST00000696920.1:n.5301A>G

ENST00000696921.1:n.6144A>G

ENST00000696922.1:n.5447A>G

ENST00000696923.1:c.5038A>G

ENST00000696924.1:c.5038A>G

ENST00000696925.1:n.5447A>G

ENST00000343455.8:c.5038A>G

ENST00000393063.6:c.5038A>G

ENST00000526495.6:c.5038A>G

ENST00000532939.3:c.5038A>G

ENST00000556045.6:c.5038A>G

ENST00000675540.1:c.2783A>G

ENST00000675995.1:c.*3354A>G

ENST00000343455.7:c.5038A>G

ENST00000393063.5:c.5038A>G

ENST00000526495.5:c.5038A>G

ENST00000527414.5:c.5038A>G

ENST00000532939.2:c.1073A>G

ENST00000541352.5:c.5038A>G

ENST00000556045.5:c.1732A>G

NM_001195573.1:c.5038A>G

NM_001271282.2:c.5038A>G

NM_001291628.1:c.5038A>G

NM_030621.4:c.5038A>G

NM_177438.2:c.5038A>G

NM_001271282.3:c.5038A>G

NM_001291628.2:c.5038A>G

NM_001395677.1:c.5038A>G

NM_001395678.1:c.5038A>G

NM_001395679.1:c.5038A>G

NM_001395680.1:c.5038A>G

NM_001395682.1:c.5038A>G

NM_001395683.1:c.5038A>G

NM_001395684.1:c.5038A>G

NM_001395685.1:c.5038A>G

NM_001395686.1:c.4756A>G

NM_001395687.1:c.4633A>G

NM_001395688.1:c.4633A>G

NM_001395689.1:c.4633A>G

NM_001395690.1:c.4633A>G

NM_001395691.1:c.4471A>G

NM_001395692.1:c.5038A>G

NM_001395693.1:c.5038A>G

NM_001395694.1:c.5038A>G

NM_001395695.1:c.5038A>G

NM_001395696.1:c.4633A>G

NM_001395697.1:c.3355A>G

NR_172715.1:n.5456A>G

NR_172716.1:n.5640A>G

NR_172717.1:n.5550A>G

NR_172718.1:n.5473A>G

NR_172719.1:n.5306A>G

NR_172720.1:n.5383A>G

Uncertain Significance

BS2_Supporting

BS4 BS3 BS1 BP7 BP5 BP2 BP3 BP4 BP1 BA1 PS1 PS3 PS4 PS2 PP1 PP3 PP2 PM6 PM2 PM5 PM1 PM3 PM4 PVS1

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.2:c.5038A>G (p.Lys1680Glu) variant in DICER1 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 1680 (p.Lys1680Glu). The total allele frequency in gnomAD v4.1.0 is 0.000003420 (5/1461878 alleles) with highest population minor allele frequencies of 0.00004967 (3/60396 alleles) and 0.000001799 (2/1111996) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.697, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). 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 data). 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: BS2_Supporting. (Bayesian Points: -1; VCEP specifications version 1.3.0; 02/27/2024)

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: 500031).

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

The total allele frequency in gnomAD v4.1.0 is 0.000003420 (5/1461878 alleles) with highest population minor allele frequencies of 0.00004967 (3/60396 alleles) and 0.000001799 (2/1111996) in a population of undescribed ancestry and the European (non-Finnish) population, respectively (PM2_Supporting, BS1, and BA1 are not met).

BP7

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.

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 0.697, 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.

BA1

PS1

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

This variant received a total of 0 phenotype points across all reported probands. (PS4 not met; GTR IDs: 61756, 500031).

PS2

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 0.697, 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.

PM6

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

PM2

PM5

2 different missense variants, c.5038A>C (p.Lys1680Gln) and c.5040G>C (p.Lys1680Asn), in the same codon have been reported (ClinVar Variation ID: 825389 and 642903). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).

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)

PM3

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

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

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