14-95108014-G-A

Position:

• chr14-95108014-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_Supporting PP1_Moderate PP4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). 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-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe 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; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID:37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA129336/MONDO:0100216/024

• Frequency: Genomes: not found (cov: 32)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 3.23

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.2516C>T	p.Ser839Phe	missense_variant	16/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.2516C>T	p.Ser839Phe	missense_variant	16/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PS3, PM2, PP1, PP3, BP1 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Jan 09, 2024	The NM_177438.2:c.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). 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-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe 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; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID: 37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 839 of the DICER1 protein (p.Ser839Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DICER1 syndrome (PMID: 21205968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Euthyroid goiter Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 05, 2011

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2020

The p.S839F variant (also known as c.2516C>T), located in coding exon 15 of the DICER1 gene, results from a C to T substitution at nucleotide position 2516. The serine at codon 839 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been identified in family with non toxic multi-nodular goiter (Rio Frio T et al. JAMA, 2011 Jan;305:68-77). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	.;.;D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.34	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D;D
Polyphen		0.83	P;P;P;P;.
Vest4		0.75
MutPred		0.60		Loss of catalytic residue at S839 (P = 0.0447);Loss of catalytic residue at S839 (P = 0.0447);Loss of catalytic residue at S839 (P = 0.0447);Loss of catalytic residue at S839 (P = 0.0447);Loss of catalytic residue at S839 (P = 0.0447);
MVP		0.95
MPC		1.0
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.74

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: rs387906934; hg19: chr14-95574351;