NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg) AND DICER1-related tumor predisposition

Germline classification:: Benign (4 submissions)
Last evaluated:: Aug 22, 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:: RCV000231396.25

Allele description [Variation Report for NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)]

NM_177438.3(DICER1):c.1124C>G (p.Pro375Arg)

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.1124C>G (p.Pro375Arg)

Other names:

NM_177438.3(DICER1):c.1124C>G; p.Pro375Arg

HGVS:

NC_000014.9:g.95124448G>C
NG_016311.1:g.37975C>G
NM_001195573.1:c.1124C>G
NM_001271282.3:c.1124C>G
NM_001291628.2:c.1124C>G
NM_030621.4:c.1124C>G
NM_177438.3:c.1124C>GMANE SELECT
NP_001182502.1:p.Pro375Arg
NP_001258211.1:p.Pro375Arg
NP_001278557.1:p.Pro375Arg
NP_085124.2:p.Pro375Arg
NP_803187.1:p.Pro375Arg
NP_803187.1:p.Pro375Arg
LRG_492t1:c.1124C>G
LRG_492:g.37975C>G
LRG_492p1:p.Pro375Arg
NC_000014.8:g.95590785G>C
NM_030621.4:c.1124C>G
NM_177438.2:c.1124C>G
p.P375R

Protein change:

P375R

Links:

dbSNP: rs148758903

NCBI 1000 Genomes Browser:

rs148758903

Molecular consequence:

NM_001195573.1:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001271282.3:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291628.2:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_030621.4:c.1124C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_177438.3:c.1124C>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
SCV000291603	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 2, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000389766	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000891032	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Likely benign (Oct 7, 2020)	germline	clinical testing	Citation Link,
SCV004032135	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen DICER1 ACMG Specifications DICER1 V1.2.0)	Benign (Aug 22, 2023)	germline	curation	Citation Link

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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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

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, SCV000291603.12

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

#	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 Illumina Laboratory Services, Illumina, SCV000389766.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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 St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV000891032.2

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

Description

The DICER1 c.1124C>G (p.Pro375Arg) missense change has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95590785-G-C). This population frequency is higher than expected for DICER1-related cancer predisposition syndrome (BS1, PMID: 24761742). Although this variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533), but in silico tools are not in agreement about the effect of this variant on protein function. This variant has been reported in an individual with papillary thyroid carcinoma whose tumor harbored a somatic DICER1 p.D1810Y variant and loss of the allele that carried the germline p.P375R variant (BP5; PMID: 29474644). This suggests that this variant is not deleterious. To our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP5, PP2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	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, SCV004032135.1

#	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.1124C>G variant in DICER1 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 375 (p.Pro375Arg). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors, PMIDs 29641532, 33630087). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004911 (58/118098 alleles) in the European (non-Finnish) population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met). The computational predictor REVEL gives a score of 0.578, 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 benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2. (Bayesian Points: -8; VCEP specifications version 1.2.0; 08/22/23).

#	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: Apr 20, 2025

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