ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1206C>T (p.Ser402=)

gnomAD frequency: 0.00001  dbSNP: rs752679968
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV001523806 SCV001478171 likely pathogenic Retinoblastoma 2020-12-15 criteria provided, single submitter research
Invitae RCV001523806 SCV003244709 uncertain significance Retinoblastoma 2023-10-06 criteria provided, single submitter clinical testing This sequence change affects codon 402 of the RB1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RB1 protein. This variant is present in population databases (rs752679968, gnomAD 0.01%). This variant has been observed in individual(s) with retinoblastoma (PMID: 21763628, 34308366). ClinVar contains an entry for this variant (Variation ID: 995890). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 21763628). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003166626 SCV003871056 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-20 criteria provided, single submitter clinical testing The c.1206C>T variant (also known as p.S402S), located in coding exon 12 of the RB1 gene, results from a C to T substitution at nucleotide position 1206. This nucleotide substitution does not change the at codon 402. This alteration has been observed in probands with unilateral retinoblastoma (Ahani A et al. Cancer Genet, 2011 Jun;204:316-22; Lan X et al. Front Genet, 2020 Mar;11:142; Fiala EM et al. Nat Cancer, 2021 Mar;2:357-365). RNA analysis showed this alteration resulted in a transcript that removed exon 12 (Ahani A et al. Cancer Genet, 2011 Jun;204:316-22). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001523806 SCV004848757 likely pathogenic Retinoblastoma 2022-08-26 criteria provided, single submitter clinical testing The p.Ser402Ser (c.1206C>T) variant in RB1 has been reported in at least 2 individuals with retinoblastoma (Ahani 2011 PMID: 21763628, Fiala 2021 PMID: 34308366) and in ClinVar (Variation ID 995890). It has been identified in 2/4830 of South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Functional assays using patient mRNA show exon skipping of exon 12 (Ahani 2011 PMID: 21763628) and loss of heterozygosity in the tumor (Fiala 2021 PMID: 34308366). Loss of function of the RB1 gene is an established disease mechanism in autosomal dominant retinoblastoma. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant retinoblastoma. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PS3.
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine RCV001523806 SCV005046087 uncertain significance Retinoblastoma 2024-05-20 criteria provided, single submitter clinical testing Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:1, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:

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