NM_001195573.1(DICER1):c.2523A>G (p.Gln841=) AND DICER1-related tumor predisposition

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003151392.2

Allele description

NM_001195573.1(DICER1):c.2523A>G (p.Gln841=)

Gene:

DICER1:dicer 1, ribonuclease III [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Preferred name:

NM_001195573.1(DICER1):c.2523A>G (p.Gln841=)

Other names:

NM_177438.3(DICER1):c.2523A>G; p.Gln841=

HGVS:

NC_000014.9:g.95108007T>C
NG_016311.1:g.54416A>G
NM_001195573.1:c.2523A>G
NM_001271282.3:c.2523A>G
NM_001291628.2:c.2523A>G
NM_030621.4:c.2523A>G
NM_177438.3:c.2523A>GMANE SELECT
NP_001182502.1:p.Gln841=
NP_001258211.1:p.Gln841=
NP_001278557.1:p.Gln841=
NP_085124.2:p.Gln841=
NP_803187.1:p.Gln841=
LRG_492:g.54416A>G
NC_000014.8:g.95574344T>C
NC_000014.8:g.95574344T>C

Links:

dbSNP: rs1891604387

Condition(s)

Name:: DICER1-related tumor predisposition
Synonyms:: DICER1-related pleuropulmonary blastoma cancer predisposition syndrome; DICER1 syndrome
Identifiers:: MONDO: MONDO:0100216; MedGen: C3839822

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003840194	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 VCEP v1.1.0)	Uncertain significance (Feb 28, 2023)	germline	curation	Citation Link,
SCV004247593	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003840194

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen DICER1 VCEP v1.1.0)

Uncertain significance
(Feb 28, 2023)

germline

curation

Citation Link,

SCV004247593

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 14, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen, SCV003840194.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_177438.3:c.2523A>G is a synonymous variant (p.Gln841=) that is predicted to impact splicing. The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1 syndrome (PP4, PPB Registry, c.5125G>A (p.D1709N)). This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Children's Minnesota). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 and miRNA-Processing Gene VCEP: PS4_Supporting, PM2_Supporting, PP3, PP4 (Bayesian Points: 4, VCEP specifications version 1.1.0; 2/28/2023).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004247593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change affects codon 841 of the DICER1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DICER1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1676595). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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