rs1060503625

chr14-95091289-G-Achr14-95091289-G-Cchr14-95091289-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_177438.3(DICER1):c.5441C>T(p.Ser1814Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1814A) has been classified as Uncertain significance.

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_177438.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DICER1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 14-95091289-G-A is Pathogenic according to our data. Variant chr14-95091289-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 412119.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-95091289-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.5441C>T	p.Ser1814Leu	missense_variant	25/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.5441C>T	p.Ser1814Leu	missense_variant	25/27	1	NM_177438.3	P1

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

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

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, 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). -
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 -

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
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

Other links and lift over

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