ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.59C>T (p.Pro20Leu)

gnomAD frequency: 0.00011  dbSNP: rs587778637
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477348 SCV000551840 likely benign Retinoblastoma 2024-01-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569325 SCV000674710 likely benign Hereditary cancer-predisposing syndrome 2022-10-24 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.
Mendelics RCV000477348 SCV000838917 uncertain significance Retinoblastoma 2018-07-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000121915 SCV000967518 uncertain significance not specified 2020-04-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Sema4, Sema4 RCV000569325 SCV002530857 likely benign Hereditary cancer-predisposing syndrome 2021-06-18 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003945101 SCV004757335 uncertain significance RB1-related disorder 2023-12-31 criteria provided, single submitter clinical testing The RB1 c.59C>T variant is predicted to result in the amino acid substitution p.Pro20Leu. This variant was reported in an individual with retinoblastoma (Parma et al. 2017. PubMed ID: 29261756, described as g.2118C>T), but was also found in the patient's asymptomatic mother and has been reported in a healthy ancestrally diverse cohort (Bodian et al. 2014. PubMed ID: 24728327, supplementary data). This variant was also described as a variant of uncertain significance in cohort of individuals with breast cancer (Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/135115/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV000477348 SCV004846298 uncertain significance Retinoblastoma 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 20 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with retinoblastoma (PMID: 12541220, 14722923, 16343894, 29261756), but also in unaffected individuals (PMID: 16343894, 24728327, 29261756). This variant has been identified in 16/132530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ITMI RCV000121915 SCV000086120 not provided not specified 2013-09-19 no assertion provided reference population

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