NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu) AND DICER1-related tumor predisposition

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 10, 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:: RCV000527854.9

Allele description [Variation Report for NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu)]

NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.13

Genomic location:

Preferred name:

NM_177438.3(DICER1):c.5259C>G (p.Asp1753Glu)

Other names:

NM_177438.3(DICER1):c.5259C>G; p.Asp1753Glu

HGVS:

NC_000014.9:g.95093993G>C
NG_016311.1:g.68430C>G
NM_001195573.1:c.5259C>G
NM_001271282.3:c.5259C>G
NM_001291628.2:c.5259C>G
NM_030621.4:c.5259C>G
NM_177438.3:c.5259C>GMANE SELECT
NP_001182502.1:p.Asp1753Glu
NP_001258211.1:p.Asp1753Glu
NP_001278557.1:p.Asp1753Glu
NP_085124.2:p.Asp1753Glu
NP_803187.1:p.Asp1753Glu
NP_803187.1:p.Asp1753Glu
LRG_492t1:c.5259C>G
LRG_492:g.68430C>G
LRG_492p1:p.Asp1753Glu
NC_000014.8:g.95560330G>C
NM_177438.2:c.5259C>G

Protein change:

D1753E

Links:

dbSNP: rs1165221864

NCBI 1000 Genomes Browser:

rs1165221864

Molecular consequence:

NM_001195573.1:c.5259C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001271282.3:c.5259C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.5259C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.5259C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.5259C>G - missense variant - [Sequence Ontology: SO:0001583]

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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Mus musculus DNA segment, Chr 2, ERATO Doi 750, expressed, mRNA (cDNA clone MGC:...
Mus musculus DNA segment, Chr 2, ERATO Doi 750, expressed, mRNA (cDNA clone MGC:30961 IMAGE:4021550), complete cds
gi|21594750|gb|BC031709.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000658339	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004015118	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 ACMG Specifications DICER1 V1.2.0)	Uncertain significance (Jul 10, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658339

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 28, 2022)

germline

clinical testing

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

SCV004015118

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

reviewed by expert panel

(ClinGen DICER1 ACMG Specifications DICER1 V1.2.0)

Uncertain significance
(Jul 10, 2023)

germline

curation

Citation Link

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 Invitae, SCV000658339.5

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1753 of the DICER1 protein (p.Asp1753Glu). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 477252).

#	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 ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen, SCV004015118.1

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

Description

The NM_177438.2:c.5259C>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 1753 (p.Asp1753Glu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_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). 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: PM2_Supporting, PM1_Supporting. (Bayesian Points: 2; VCEP specifications version 1.2.0; 07/10/2023)

#	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

Last Updated: Sep 16, 2024

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