ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.2566G>T (p.Asp856Tyr)

dbSNP: rs149359120
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001042193 SCV001205860 uncertain significance Retinoblastoma 2023-09-21 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 840248). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 856 of the RB1 protein (p.Asp856Tyr).
Sema4, Sema4 RCV002258096 SCV002530838 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter curation
Ambry Genetics RCV002258096 SCV002738867 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing The p.D856Y variant (also known as c.2566G>T), located in coding exon 25 of the RB1 gene, results from a G to T substitution at nucleotide position 2566. The aspartic acid at codon 856 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well 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.
All of Us Research Program, National Institutes of Health RCV001042193 SCV004844757 uncertain significance Retinoblastoma 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 856 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251282 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.

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