ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.4804G>A (p.Ala1602Thr)

gnomAD frequency: 0.00011  dbSNP: rs145669719
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457948 SCV000553509 likely benign DICER1-related tumor predisposition 2024-01-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561152 SCV000661815 likely benign Hereditary cancer-predisposing syndrome 2024-04-19 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 RCV000457948 SCV001761643 uncertain significance DICER1-related tumor predisposition 2021-06-17 criteria provided, single submitter clinical testing The DICER1 c.4804G>A (p.Ala1602Thr) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95562453-C-T?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. Although this variant occurs in a gene where missense variants are more likely to be damaging (PMID: 27535533), the variant lies at a residue that has a constrained coding region score of 0 and is not predicted to be more damaging based on methods described by Havrilla et al (PMID: 30531870). This variant was identified in 1/1358 non-cancer control individuals in a study of individuals with multiple primary cancers (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with DICER1 syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4 RCV000561152 SCV002533023 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-02 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268092 SCV002551485 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing

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