Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000467333 | SCV000551836 | likely benign | Retinoblastoma | 2023-12-27 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001015689 | SCV001176551 | likely benign | Hereditary cancer-predisposing syndrome | 2022-12-28 | 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479127 | SCV004222659 | uncertain significance | not specified | 2023-11-15 | criteria provided, single submitter | clinical testing | Variant summary: RB1 c.2491A>G (p.Ile831Val) results in a conservative amino acid change located in the Retinoblastoma-associated protein, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 1574358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RB1 causing Retinoblastoma (1.5e-05 vs 4.2e-05), allowing no conclusion about variant significance. c.2491A>G has been reported in the literature in individuals affected with unspecified cancer (deOliveira_2022). This report does not provide unequivocal conclusions about association of the variant with Retinoblastoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| All of Us Research Program, |
RCV000467333 | SCV004844750 | uncertain significance | Retinoblastoma | 2023-12-07 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 831 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 RB1-related disorders in the literature. This variant has been identified in 5/250614 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. |