VCV000242032.12 - ClinVar

NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)

Interpretation:: Conflicting interpretations of pathogenicity
Benign(2);Likely benign(2);Uncertain significance(2)
Review status:: criteria provided, conflicting interpretations
Submissions:: 6 (Most recent: Aug 30, 2021)
Last evaluated:: Dec 2, 2020
Accession:: VCV000242032.12
Variation ID:: 242032
Description:: single nucleotide variant

NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)

Allele ID

241997

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

14q32.13

Genomic location

14: 95124448 (GRCh38) GRCh38 UCSC

14: 95590785 (GRCh37) GRCh37 UCSC

HGVS

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

... more HGVS ... less HGVS

Protein change

P375R

Other names

Canonical SPDI

NC_000014.9:95124447:G:C

Functional consequence

Global minor allele frequency (GMAF)

0.00020 (C)

Allele frequency

The Genome Aggregation Database (gnomAD) 0.00019

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00025

The Genome Aggregation Database (gnomAD), exomes 0.00035

Exome Aggregation Consortium (ExAC) 0.00035

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

Links

ClinGen: CA7331526

dbSNP: rs148758903

Varsome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
DICER1-related pleuropulmonary blastoma cancer predisposition syndrome	Benign/Likely benign	3	criteria provided, multiple submitters, no conflicts	Dec 2, 2020	RCV000231396.10
Hereditary cancer-predisposing syndrome	Uncertain significance	1	criteria provided, single submitter	Oct 14, 2018	RCV000570796.1
not specified	Benign	1	criteria provided, single submitter	Jul 1, 2019	RCV001201043.2
Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors	Uncertain significance	1	criteria provided, single submitter	Apr 10, 2020	RCV001292801.1

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
DICER1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3396	3417

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	Supporting information (See all)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	DICER1-related pleuropulmonary blastoma cancer predisposition syndrome Allele origin: germline	Illumina Clinical Services Laboratory,Illumina Accession: SCV000389766.3 Submitted: (Feb 20, 2020)	Evidence details Comment: 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 … (more) 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. (less)
Likely benign (Dec 02, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	DICER1-related pleuropulmonary blastoma cancer predisposition syndrome Allele origin: germline	Invitae Accession: SCV000291603.8 Submitted: (Jan 07, 2021)	Evidence details Publications PubMed (1)
Uncertain significance (Oct 14, 2018)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (3/2017)) Method: clinical testing	Hereditary cancer-predisposing syndrome Allele origin: germline	Ambry Genetics Accession: SCV000661811.3 Submitted: (Nov 30, 2020)	Evidence details Comment: The p.P375R variant (also known as c.1124C>G), located in coding exon 7 of the DICER1 gene, results from a C to G substitution at nucleotide … (more) The p.P375R variant (also known as c.1124C>G), located in coding exon 7 of the DICER1 gene, results from a C to G substitution at nucleotide position 1124. The proline at codon 375 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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. (less)
Likely benign (Oct 07, 2020)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	DICER1-related pleuropulmonary blastoma cancer predisposition syndrome Allele origin: germline	St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital Accession: SCV000891032.2 Submitted: (Dec 15, 2020)	Evidence details Comment: 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 … (more) 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. (less)
Uncertain significance (Apr 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors Allele origin: paternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481455.2 Submitted: (Feb 10, 2021)	Evidence details Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Benign (Jul 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Not Specified Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Accession: SCV001372045.2 Submitted: (Aug 30, 2021)	Evidence details Publications PubMed (1) Comment: ACMG criteria met: PP5, BS1, BS2, BP1

Comment:

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.

Comment:

The p.P375R variant (also known as c.1124C>G), located in coding exon 7 of the DICER1 gene, results from a C to G substitution at nucleotide position 1124. The proline at codon 375 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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.

Comment:

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.

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
DICER1 Mutations Are Frequent in Adolescent-Onset Papillary Thyroid Carcinoma.	Wasserman JD	The Journal of clinical endocrinology and metabolism	2018	PMID: 29474644
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.	Nykamp K	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492532

Text-mined citations for rs148758903...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 07, 2021

ClinVar Genomic variation as it relates to human health

NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)

NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs148758903...