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

gnomAD frequency: 0.00025  dbSNP: rs148758903

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV000231396	SCV004032135	benign	DICER1-related tumor predisposition	2023-08-22	reviewed by expert panel	curation	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).
Invitae	RCV000231396	SCV000291603	benign	DICER1-related tumor predisposition	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000231396	SCV000389766	benign	DICER1-related tumor predisposition	2018-01-12	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000570796	SCV000661811	likely benign	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000231396	SCV000891032	likely benign	DICER1-related tumor predisposition	2020-10-07	criteria provided, single submitter	clinical testing	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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001201043	SCV001372045	benign	not specified	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PP5, BS1, BS2, BP1
Baylor Genetics	RCV001292801	SCV001481455	uncertain significance	Euthyroid goiter	2020-04-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002469086	SCV002010938	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570796	SCV002532439	likely benign	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001201043	SCV002551564	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002469086	SCV002765203	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with CNS sarcoma, thyroid, and other cancers, but also in unaffected controls (Slade 2011, Mandelker 2017, Pritchard 2018, Wasserman 2018, Kamihara 2020); This variant is associated with the following publications: (PMID: 21266384, 29474644, 28873162, 29641532, 28748527, 32291395)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002469086	SCV002774143	likely benign	not provided	2023-08-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002469086	SCV004130334	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	DICER1: PP2, BS1
PreventionGenetics, part of Exact Sciences	RCV003977693	SCV004795607	likely benign	DICER1-related disorder	2022-04-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genetic Services Laboratory, University of Chicago	RCV001201043	SCV003839422	uncertain significance	not specified	2022-05-09	no assertion criteria provided	clinical testing	DNA sequence analysis of the DICER1 gene demonstrated a sequence change, c.1124C>G, in exon 8 that results in an amino acid change, p.Pro375Arg. This sequence change does not appear to have been previously described in individuals with DICER1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.050% in the European subpopulation (dbSNP rs148758903). The p.Pro375Arg change affects a highly conserved amino acid residue located in a domain of the DICER1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro375Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro375Arg change remains unknown at this time.