Submissions for variant NM_000321.3(RB1):c.1861C>T (p.Arg621Cys)

dbSNP: rs367578442

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460516	SCV000551835	benign	Retinoblastoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565788	SCV000674718	benign	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000460516	SCV001270239	likely benign	Retinoblastoma	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001821287	SCV002070633	uncertain significance	not specified	2021-08-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RB1 gene demonstrated a sequence change, c.1861C>T, in exon 19 that results in an amino acid change, p.Arg621Cys. This sequence change has been described in the gnomAD database with a frequency of 0.014% in the non-Finnish European subpopulation (dbSNP rs367578442). The p.Arg621Cys change affects a moderately conserved amino acid residue located in a domain of the RB1 protein that is not known to be functional. The p.Arg621Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been described in individuals with retinoblastoma, however it has been reported in an individual with breast cancer and in vitro experimental studies indicated that this variant was unable to induce apoptosis in cultured cells (PMID: 20594292). A different amino acid change at this same position, p.Arg621Ser, has been reported in a 5-month-old individual with unilateral retinoblastoma. Due to insufficient evidences, the clinical significance of the p.Arg621Cys change remains unknown at this time.