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]

Variant: NM_177438.3(DICER1):c.4475T>C (p.Met1492Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA7330841

483407 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e3240901-955d-46f6-80c5-f71521a2da1b

Approved on: 2024-02-27

Published on: 2024-05-08

HGVS expressions

NM_177438.3:c.4475T>C

NM_177438.3(DICER1):c.4475T>C (p.Met1492Thr)

NC_000014.9:g.95096445A>G

CM000676.2:g.95096445A>G

NC_000014.8:g.95562782A>G

CM000676.1:g.95562782A>G

NC_000014.7:g.94632535A>G

NG_016311.1:g.65978T>C

ENST00000529720.2:c.4475T>C

ENST00000531162.7:c.4475T>C

ENST00000674628.2:c.4475T>C

ENST00000675540.2:c.*1125T>C

ENST00000696733.1:c.4475T>C

ENST00000696734.1:c.4475T>C

ENST00000696735.1:n.1462T>C

ENST00000696736.1:c.4475T>C

ENST00000696737.1:c.4475T>C

ENST00000696920.1:n.4738T>C

ENST00000696921.1:n.5581T>C

ENST00000696922.1:n.4884T>C

ENST00000696923.1:c.4475T>C

ENST00000696924.1:c.4475T>C

ENST00000696925.1:n.4884T>C

ENST00000343455.8:c.4475T>C

ENST00000393063.6:c.4475T>C

ENST00000526495.6:c.4475T>C

ENST00000532939.3:c.4475T>C

ENST00000556045.6:c.4475T>C

ENST00000675540.1:c.2220T>C

ENST00000675995.1:c.*2791T>C

ENST00000343455.7:c.4475T>C

ENST00000393063.5:c.4475T>C

ENST00000526495.5:c.4475T>C

ENST00000527414.5:c.4475T>C

ENST00000532939.2:c.510T>C

ENST00000541352.5:c.4475T>C

ENST00000556045.5:c.1169T>C

NM_001195573.1:c.4475T>C

NM_001271282.2:c.4475T>C

NM_001291628.1:c.4475T>C

NM_030621.4:c.4475T>C

NM_177438.2:c.4475T>C

NM_001271282.3:c.4475T>C

NM_001291628.2:c.4475T>C

NM_001395677.1:c.4475T>C

NM_001395678.1:c.4475T>C

NM_001395679.1:c.4475T>C

NM_001395680.1:c.4475T>C

NM_001395682.1:c.4475T>C

NM_001395683.1:c.4475T>C

NM_001395684.1:c.4475T>C

NM_001395685.1:c.4475T>C

NM_001395686.1:c.4193T>C

NM_001395687.1:c.4070T>C

NM_001395688.1:c.4070T>C

NM_001395689.1:c.4070T>C

NM_001395690.1:c.4070T>C

NM_001395691.1:c.3908T>C

NM_001395692.1:c.4475T>C

NM_001395693.1:c.4475T>C

NM_001395694.1:c.4475T>C

NM_001395695.1:c.4475T>C

NM_001395696.1:c.4070T>C

NM_001395697.1:c.2792T>C

NR_172715.1:n.4893T>C

NR_172716.1:n.5077T>C

NR_172717.1:n.4987T>C

NR_172718.1:n.4910T>C

NR_172719.1:n.4743T>C

NR_172720.1:n.4820T>C

Likely Benign

BS2_Supporting BP4

PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM1 PM5 BA1 PM2 BS4 BS3 BS1

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.4475T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 1492 (p.Met1492Thr). 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). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.049; MaxEntScan and SpliceAI: no effect on splicing) (BP4). The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1614146 alleles) with highest population minor allele frequencies of 0.00001334 (1/74954alleles) and 0.000002542 (3/1180050) in the African American and European (non-Finnish) populations, respectively (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; 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; Internal lab contributors).

BP4

In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.049; MaxEntScan and SpliceAI: no effect on splicing) (BP4).

PS2

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

PS4

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

PS1

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

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

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).

PM5

2 different missense variants, (c.4476G>A, p.Met1492Ile and c.4474A>G, p.Met1492Val), in the same codon have been reported (ClinVar Variation ID: 950511, 477207). However, these variants have not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).

BA1

The total allele frequency in gnomAD v4.1.0 is 0.000002478 (4/1614146 alleles) with highest population minor allele frequencies of 0.00001334 (1/74954alleles) and 0.000002542 (3/1180050) in the African American and European (non-Finnish) populations, respectively (PM2_Supporting, BS1, and BA1 are not met).

PM2

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

Curation History

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