ClinVar Miner

Submissions for variant NM_177438.2(DICER1):c.1124C>G (p.Pro375Arg) (rs148758903)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231396 SCV000291603 likely benign DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 2020-12-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000231396 SCV000389766 benign DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 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 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-14 criteria provided, single submitter clinical testing 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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000231396 SCV000891032 likely benign DICER1-related pleuropulmonary blastoma cancer predisposition syndrome 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 ( 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.
Baylor Genetics RCV001292801 SCV001481455 uncertain significance Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors 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].
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV001201043 SCV001372045 benign not specified 2019-07-01 no assertion criteria provided literature only

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