NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu) AND DICER1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 25, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003389645.4

Allele description [Variation Report for NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu)]

NM_177438.3(DICER1):c.5441C>T (p.Ser1814Leu)

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.5441C>T (p.Ser1814Leu)

Other names:

NM_030621.4(DICER1):c.5441C>T; p.Ser1814Leu

HGVS:

NC_000014.9:g.95091289G>A
NG_016311.1:g.71134C>T
NM_001195573.1:c.5365-180C>T
NM_001271282.3:c.5441C>T
NM_001291628.2:c.5441C>T
NM_030621.4:c.5441C>T
NM_177438.3:c.5441C>TMANE SELECT
NP_001258211.1:p.Ser1814Leu
NP_001278557.1:p.Ser1814Leu
NP_085124.2:p.Ser1814Leu
NP_803187.1:p.Ser1814Leu
NP_803187.1:p.Ser1814Leu
LRG_492t1:c.5441C>T
LRG_492:g.71134C>T
LRG_492p1:p.Ser1814Leu
NC_000014.8:g.95557626G>A
NM_177438.2:c.5441C>T
p.S1814L

Protein change:

S1814L

Links:

dbSNP: rs1060503625

NCBI 1000 Genomes Browser:

rs1060503625

Molecular consequence:

NM_001195573.1:c.5365-180C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001271282.3:c.5441C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.5441C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.5441C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.5441C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: DICER1-related disorder
Synonyms:: DICER1-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000993768	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 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

SCV000993768

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 25, 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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV000993768.2

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

Description

The DICER1 c.5441C>T variant is predicted to result in the amino acid substitution p.Ser1814Leu. This variant has been reported to segregate in a family with DICER1-syndrome (Rutter et al. 2016. PubMed ID: 26555935) and reported in an additional unrelated individual with DICER1-syndrome (Wu et al. 2016. PubMed ID: 26545620). It has been reported in an individual with a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing (Rutter et al. 2016. PubMed ID: 26555935). Functional studies suggest this variant may lead to exon skipping and impact pre-miR122 cleavage (Figure 2, Wu et al. 2016. PubMed ID: 26545620). This variant occurs in the RNase IIIb domain, which is a hotspot for missense variants associated with DICER1-related neoplasms (Heravi-Moussavi et al. 2012. PubMed ID: 22187960; Foulkes et al. 2014. PubMed ID: 25176334; Chen et al. 2018. PubMed ID: 31893257). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic by the ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/412119/). This variant is interpreted as pathogenic.

#	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: Oct 13, 2024

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