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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 18, 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:: RCV000469249.17

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 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
SCV000553579	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26555935, 26545620, 28492532
SCV001372200	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26555935, 25741868
SCV002540835	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 ACMG Specifications DICER1 v1)	Pathogenic (May 18, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000553579

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 14, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001372200

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 1, 2019)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV002540835

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

reviewed by expert panel

(ClinGen DICER1 ACMG Specifications DICER1 v1)

Pathogenic
(May 18, 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	yes	7	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Functional characterization of multiple DICER1 mutations in an adolescent.

Wu MK, de Kock L, Conwell LS, Stewart CJ, King BR, Choong CS, Hussain K, Sabbaghian N, MacRae IJ, Fabian MR, Foulkes WD.

Endocr Relat Cancer. 2016 Feb;23(2):L1-5. doi: 10.1530/ERC-15-0460. Epub 2015 Nov 6. No abstract available.

PubMed [citation]

PMID:: 26545620

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000553579.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1814 of the DICER1 protein (p.Ser1814Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with DICER1-related disease (PMID: 26545620, 26555935; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 412119). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DICER1 function (PMID: 26545620). For these reasons, this variant has been classified 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

From Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research, SCV001372200.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	curation	PubMed (2)

Description

ACMG criteria met: PS3, PM1, PM2, PP3, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		7	not provided	not provided	not provided

From ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen, SCV002540835.1

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

Description

NM_177438.2(DICER1):c.5441C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by leucine at amino acid 1814 (p.Ser1814Leu). This variant received a total of 4.5 phenotype points across 5 unrelated probands/families meeting DICER1 VCEP phenotype specificity scoring criteria of >4 points (PS4; PMIDs: 26545620, 26555935, ClinVar GTRs: 239772, 500031, 500086). 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, PMIDs: 26555935). The variant has been reported to segregate with disease in multiple affected family members with 7 meioses from 3 families (PP1_Strong; PMIDs: 26555935, ClinVar SCVs: SCV000553579.6). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer)(PM2_Supporting). In vitro cleavage assay in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 26545620). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functional as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.889, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4, PP4, PP1_Strong, PM2_Supporting, PS3_Supporting, PM1_Supporting, PP3 (Bayesian Points: 13; VCEP specifications version 1; 02/11/2022).

#	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: Nov 24, 2024

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