Submissions for variant NM_177438.3(DICER1):c.59C>T (p.Ala20Val)

gnomAD frequency: 0.00070  dbSNP: rs147660793

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV000203871	SCV002540816	benign	DICER1-related tumor predisposition	2022-05-18	reviewed by expert panel	curation	The NM_177438.2:c.59C>T is a missense variant in DICER1 predicted to cause substitution of Alanine by Valine at amino acid 20 (p.Ala20Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0009673 in the non-Finnish European population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (Internal lab contributors GTRs: 61756, 500031) and has been observed in a homozygous state in 3 healthy individuals (Internal lab contributors GTR: 500031)(BS2). The computational predictor REVEL gives a score of 0.302, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). 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, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203871	SCV000262365	benign	DICER1-related tumor predisposition	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203871	SCV000389772	benign	DICER1-related tumor predisposition	2018-01-13	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	RCV000493114	SCV000581547	likely benign	Hereditary cancer-predisposing syndrome	2022-03-28	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.
GeneDx	RCV001356132	SCV001830614	likely benign	not provided	2021-05-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28873162, 24728327)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001356132	SCV002049311	likely benign	not provided	2021-04-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000493114	SCV002533077	likely benign	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120633	SCV002551576	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120633	SCV002774235	benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001356132	SCV004699863	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	DICER1: BS1
Breakthrough Genomics, Breakthrough Genomics	RCV001356132	SCV005210871	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120633	SCV000084794	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356132	SCV001551205	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965011	SCV004782955	benign	DICER1-related disorder	2024-03-14	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).