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.925G>A (p.Val309Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA390887361

477295 (ClinVar)

Gene: DICER1

Condition: DICER1-related tumor predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e61b6012-2338-41cc-8838-5c9c4f950cea

Approved on: 2024-04-23

Published on: 2024-05-08

HGVS expressions

NM_177438.3:c.925G>A

NM_177438.3(DICER1):c.925G>A (p.Val309Ile)

NC_000014.9:g.95124647C>T

CM000676.2:g.95124647C>T

NC_000014.8:g.95590984C>T

CM000676.1:g.95590984C>T

NC_000014.7:g.94660737C>T

NG_016311.1:g.37776G>A

ENST00000529720.2:c.925G>A

ENST00000531162.7:c.925G>A

ENST00000674628.2:c.925G>A

ENST00000675540.2:c.925G>A

ENST00000696733.1:c.925G>A

ENST00000696734.1:c.925G>A

ENST00000696736.1:c.925G>A

ENST00000696737.1:c.925G>A

ENST00000696921.1:n.2031G>A

ENST00000696922.1:n.1334G>A

ENST00000696923.1:c.925G>A

ENST00000696924.1:c.925G>A

ENST00000696925.1:n.1334G>A

ENST00000696927.1:n.528G>A

ENST00000696928.1:n.1122G>A

ENST00000343455.8:c.925G>A

ENST00000393063.6:c.925G>A

ENST00000526495.6:c.925G>A

ENST00000532939.3:c.925G>A

ENST00000556045.6:c.925G>A

ENST00000674628.1:c.925G>A

ENST00000675995.1:c.925G>A

ENST00000343455.7:c.925G>A

ENST00000393063.5:c.925G>A

ENST00000526495.5:c.925G>A

ENST00000527414.5:c.925G>A

ENST00000541352.5:c.925G>A

NM_001195573.1:c.925G>A

NM_001271282.2:c.925G>A

NM_001291628.1:c.925G>A

NM_030621.4:c.925G>A

NM_177438.2:c.925G>A

NM_001271282.3:c.925G>A

NM_001291628.2:c.925G>A

NM_001395677.1:c.925G>A

NM_001395678.1:c.925G>A

NM_001395679.1:c.925G>A

NM_001395680.1:c.925G>A

NM_001395682.1:c.925G>A

NM_001395683.1:c.925G>A

NM_001395684.1:c.925G>A

NM_001395685.1:c.925G>A

NM_001395686.1:c.643G>A

NM_001395687.1:c.520G>A

NM_001395688.1:c.520G>A

NM_001395689.1:c.520G>A

NM_001395690.1:c.520G>A

NM_001395691.1:c.358G>A

NM_001395692.1:c.925G>A

NM_001395693.1:c.925G>A

NM_001395694.1:c.925G>A

NM_001395695.1:c.925G>A

NM_001395696.1:c.520G>A

NM_001395697.1:c.-644G>A

NM_001395698.1:c.520G>A

NM_001395699.1:c.925G>A

NM_001395700.1:c.925G>A

NR_172715.1:n.1139G>A

NR_172716.1:n.1270G>A

NR_172717.1:n.1437G>A

NR_172718.1:n.1437G>A

NR_172719.1:n.1270G>A

NR_172720.1:n.1270G>A

Likely Benign

BP4 BS2_Supporting

PM5 PM3 PM1 PM4 PM6 PM2 BA1 PVS1 BS4 BS3 BS1 BP2 BP3 BP1 BP5 BP7 PS1 PS4 PS2 PS3 PP1 PP4 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 1.3.0

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.925G>A variant in DICER1 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 309 (p.Val309Ile). 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 contributor). This variant was seen in a child with pleuropulmonary blastoma; however, the child harbored a second germline variant (c.2256+2T>C, phase unknown) in DICER1 (PS4 and BP2 not met). The total allele frequency in gnomAD v4.1.0 is 0.00001550 (25/1613198 alleles) with a highest population minor allele frequency of 0.00006669 (4/59980 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.189; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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; 04/23/2024)

BP4

In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.189; MaxEntScan and SpliceAI: no effect on splicing) (BP4).

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 contributor).

PM5

1 different missense variant, c.925G>C (p.Val309Leu), in the same codon has been reported (ClinVar Variation ID: 2911201). However, this variant has not yet met the criteria to be classified as pathogenic by the ClinGen DICER VCEP (PM5 not met).

PM3

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

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).

PM4

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

PM6

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

PM2

The total allele frequency in gnomAD v4.1.0 is 0.00001550 (25/1613198 alleles) with a highest population minor allele frequency of 0.00006669 (4/59980 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met)

BA1

PVS1

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

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

BP2

This variant has been observed in phase unknown with the variant c.2256+2T>C (Internal lab contributor) which is classified as likely pathogenic in ClinVar in an individual with DICER1-related tumor predisposition (BP2).

BP3

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

BP1

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

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

PS1

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

PS4

This variant and the DICER1 variant c.2256+2T>C (ClinVar 1066927: Likely Pathogenic by Invitae) were in unknown phase and reported together in 1 male with PPB diagnosed <18 years old.

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

PP1

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

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

PP2

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

Curation History

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