NM_177438.3(DICER1):c.4313A>G (p.Tyr1438Cys) AND DICER1-related tumor predisposition

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV001208413.9

Allele description [Variation Report for NM_177438.3(DICER1):c.4313A>G (p.Tyr1438Cys)]

NM_177438.3(DICER1):c.4313A>G (p.Tyr1438Cys)

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.4313A>G (p.Tyr1438Cys)

Other names:

NM_177438.3(DICER1):c.4313A>G; p.Tyr1438Cys

HGVS:

NC_000014.9:g.95096607T>C
NG_016311.1:g.65816A>G
NM_001195573.1:c.4313A>G
NM_001271282.3:c.4313A>G
NM_001291628.2:c.4313A>G
NM_030621.4:c.4313A>G
NM_177438.3:c.4313A>GMANE SELECT
NP_001182502.1:p.Tyr1438Cys
NP_001258211.1:p.Tyr1438Cys
NP_001278557.1:p.Tyr1438Cys
NP_085124.2:p.Tyr1438Cys
NP_803187.1:p.Tyr1438Cys
LRG_492t1:c.4313A>G
LRG_492:g.65816A>G
NC_000014.8:g.95562944T>C
NM_177438.2:c.4313A>G

Protein change:

Y1438C

Links:

dbSNP: rs1202589148

NCBI 1000 Genomes Browser:

rs1202589148

Molecular consequence:

NM_001195573.1:c.4313A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001271282.3:c.4313A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.4313A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.4313A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.4313A>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
SCV001379798	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004231834	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 (Jan 9, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001379798

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 11, 2023)

germline

clinical testing

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

SCV004231834

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
(Jan 9, 2024)

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, SCV001379798.5

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

Description

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 939082). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1438 of the DICER1 protein (p.Tyr1438Cys). 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.

#	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, SCV004231834.1

#	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.4313A>G variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 1438 (p.Tyr1438Cys). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.2; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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: PM2_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024)

#	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 18, 2024

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