rs1060503625

Variant names:

• chr14-95091289-G-A
• rs1060503625
• NM_177438.3:c.5441C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95091289-G-A
• chr14-95091289-G-C
• chr14-95091289-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3_Supporting PP3 PP4 PM2_Supporting PS4 PM1_Supporting PP1_Strong

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 NM_177438.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.38
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• DICER1-related tumor predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pleuropulmonary blastoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• DICER1 syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.5441C>T	p.Ser1814Leu	missense	Exon 25 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.5441C>T	p.Ser1814Leu	missense	Exon 25 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.5441C>T	p.Ser1814Leu	missense	Exon 25 of 27	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.5441C>T	p.Ser1814Leu	missense	Exon 25 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.5441C>T	p.Ser1814Leu	missense	Exon 27 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.5441C>T	p.Ser1814Leu	missense	Exon 25 of 27	ENSP00000435681.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 412119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DICER1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DICER1 function (PMID: 26545620). For these reasons, this variant has been classified as Pathogenic.

Jul 01, 2019

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

May 18, 2022

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Aug 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 05, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.80		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

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