rs1060503625

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PM1_SupportingPP1_StrongPS3_SupportingPP3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614268/MONDO:0017288/024

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DICER1
ENST00000343455.8 missense

Scores

17

1

1

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.38

Variant links:

Genes affected

DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]

DICER1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.5441C>T	p.Ser1814Leu	missense_variant	25/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.5441C>T	p.Ser1814Leu	missense_variant	25/27	1	NM_177438.3	ENSP00000343745	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461820

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	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. -
Pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PS3, PM1, PM2, PP3, PP4 -
Pathogenic, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	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). -

DICER1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 16, 2023

The DICER1 c.5441C>T (p.Ser1814Leu) variant has been reported in the published literature in individuals with DICER1-related disease (PMIDs: 26555935 (2016), 26545620 (2016)) and has been observed segregating with disease in related individuals (PMID: 26555935 (2016)). An experimental assay reports the variant reduces miRNA generation (PMID: 26545620 (2016)), however further evidence is needed to assess the global impact of the variant on protein function. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Euthyroid goiter;C1867234:Rhabdomyosarcoma, embryonal, 2;C3839822:DICER1-related tumor predisposition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2023

The p.S1814L pathogenic mutation (also known as c.5441C>T), located in coding exon 24 of the DICER1 gene, results from a C to T substitution at nucleotide position 5441. The serine at codon 1814 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with DICER1-associated tumors (Ambry internal data; Rutter MM et al. J. Clin. Endocrinol. Metab., 2016 Jan;101:1-5; Wu MK et al. Endocr. Relat. Cancer, 2016 Feb;23:L1-5). In addition, this variant segregated with disease in a family affected with early-onset multinodular goiters, differentiated thyroid cancer, and other DICER1-associated tumors (Rutter MM et al. J. Clin. Endocrinol. Metab., 2016 Jan;101:1-5). This variant demonstrated reduced 5p and 3p miRNA generation as compared to normal DICER1 protein in an in vitro cleavage assay (Wu MK et al. Endocr. Relat. Cancer, 2016). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

34

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

1.0

.;.;D;.;D

M_CAP

Pathogenic

0.37

D

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

4.3

H;H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.94

MutPred

0.80

Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);.;

MVP

0.95

MPC

2.3

ClinPred

1.0

D

GERP RS

4.7

Varity_R

0.98

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060503625; hg19: chr14-95557626; COSMIC: COSV58630883; COSMIC: COSV58630883;