NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser) AND DICER1-related tumor predisposition

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 25, 2022
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:: RCV000654414.8

Allele description [Variation Report for NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser)]

NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser)

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.1904A>G (p.Asn635Ser)

Other names:

NM_177438.3(DICER1):c.1904A>G; p.Asn635Ser

HGVS:

NC_000014.9:g.95115670T>C
NG_016311.1:g.46753A>G
NM_001195573.1:c.1904A>G
NM_001271282.3:c.1904A>G
NM_001291628.2:c.1904A>G
NM_030621.4:c.1904A>G
NM_177438.3:c.1904A>GMANE SELECT
NP_001182502.1:p.Asn635Ser
NP_001258211.1:p.Asn635Ser
NP_001278557.1:p.Asn635Ser
NP_085124.2:p.Asn635Ser
NP_803187.1:p.Asn635Ser
NP_803187.1:p.Asn635Ser
LRG_492t1:c.1904A>G
LRG_492:g.46753A>G
LRG_492p1:p.Asn635Ser
NC_000014.8:g.95582007T>C
NM_177438.2:c.1904A>G

Protein change:

N635S

Links:

dbSNP: rs765551529

NCBI 1000 Genomes Browser:

rs765551529

Molecular consequence:

NM_001195573.1:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001271282.3:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.1904A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.1904A>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000776308	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599122	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 VCEP v1.1.0)	Uncertain significance (Oct 25, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000776308

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

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

SCV002599122

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

reviewed by expert panel

(ClinGen DICER1 VCEP v1.1.0)

Uncertain significance
(Oct 25, 2022)

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000776308.6

#	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 replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 635 of the DICER1 protein (p.Asn635Ser). This variant is present in population databases (rs765551529, gnomAD 0.003%). 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: 479636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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

From ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen, SCV002599122.1

#	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.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Serine at amino acid 635 (p.Asp635Ser). This variant received 0 phenotype points across 16 probands, including 3 unrelated females without tumors through age 50 (GTRs: 61756, 500031, PMID: 33718253) (PS4 and BS2 are not met). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5; however, the splice site predictors MaxEntScan and SpliceAI indicate creation of a new donor splice site (BP4 and PP3 not met). 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 VCEP: No criteria. (Bayesian Points: 0; VCEP specifications version 1.1.0; 10/25/2022).

#	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: Feb 14, 2024

ClinVar

Relating variation to medicine