Submissions for variant NM_000321.3(RB1):c.2557T>G (p.Cys853Gly)

dbSNP: rs1295589257

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001015955	SCV001176850	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The p.C853G variant (also known as c.2557T>G), located in coding exon 25 of the RB1 gene, results from a T to G substitution at nucleotide position 2557. The cysteine at codon 853 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration was detected in a cohort of unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363).This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003514456	SCV004268135	uncertain significance	Retinoblastoma	2022-11-13	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) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function. ClinVar contains an entry for this variant (Variation ID: 821488). This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 853 of the RB1 protein (p.Cys853Gly).
All of Us Research Program, National Institutes of Health	RCV003514456	SCV004844755	uncertain significance	Retinoblastoma	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 853 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.