NM_177438.3(DICER1):c.5461A>G (p.Met1821Val) AND DICER1-related tumor predisposition

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 10, 2023
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:: RCV000457347.8

Allele description [Variation Report for NM_177438.3(DICER1):c.5461A>G (p.Met1821Val)]

NM_177438.3(DICER1):c.5461A>G (p.Met1821Val)

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.5461A>G (p.Met1821Val)

Other names:

NM_177438.3(DICER1):c.5461A>G; p.Met1821Val

HGVS:

NC_000014.9:g.95091269T>C
NG_016311.1:g.71154A>G
NM_001195573.1:c.5365-160A>G
NM_001271282.3:c.5461A>G
NM_001291628.2:c.5461A>G
NM_030621.4:c.5461A>G
NM_177438.3:c.5461A>GMANE SELECT
NP_001258211.1:p.Met1821Val
NP_001278557.1:p.Met1821Val
NP_085124.2:p.Met1821Val
NP_803187.1:p.Met1821Val
NP_803187.1:p.Met1821Val
LRG_492t1:c.5461A>G
LRG_492:g.71154A>G
LRG_492p1:p.Met1821Val
NC_000014.8:g.95557606T>C
NM_177438.2:c.5461A>G

Protein change:

M1821V

Links:

dbSNP: rs1060503604

NCBI 1000 Genomes Browser:

rs1060503604

Molecular consequence:

NM_001195573.1:c.5365-160A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001271282.3:c.5461A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.5461A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.5461A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.5461A>G - 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
SCV000553612	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004015121	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 ACMG Specifications DICER1 V1.2.0)	Uncertain significance (Jul 10, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000553612

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 19, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004015121

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

reviewed by expert panel

(ClinGen DICER1 ACMG Specifications DICER1 V1.2.0)

Uncertain significance
(Jul 10, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000553612.6

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 412149). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1821 of the DICER1 protein (p.Met1821Val).

#	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 ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen, SCV004015121.1

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

Description

The NM_177438.2:c.5461A>G variant in DICER1 is a missense variant predicted to cause substitution of methionine by valine at amino acid 1821 (p.Met1821Val). This variant has an allele frequency of 0.000004 (1/236,934 alleles) across gnomAD v2.1.1 (non-cancer) with no more than one allele in any subpopulation, which is lower than the ClinGen DICER1 VCEP threshold (<0.000005) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.54, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, PM2_Supporting. (Bayesian Points: 2; VCEP specifications version 1.2.0; 07/10/2023)

#	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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