Submissions for variant NM_000321.3(RB1):c.2518G>A (p.Gly840Arg)

gnomAD frequency: 0.00002  dbSNP: rs374157786

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232184	SCV000284622	likely benign	Retinoblastoma	2024-01-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000232184	SCV000838928	uncertain significance	Retinoblastoma	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001015828	SCV001176706	likely benign	Hereditary cancer-predisposing syndrome	2021-09-02	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.
Sema4, Sema4	RCV001015828	SCV002530833	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003417806	SCV004106465	uncertain significance	RB1-related disorder	2022-10-26	criteria provided, single submitter	clinical testing	The RB1 c.2518G>A variant is predicted to result in the amino acid substitution p.Gly840Arg. To our knowledge, this variant has not been reported as a germline variant in an individual with RB1-related disease. It has been reported as a somatic variant in an individual with metastatic breast cancer; however, this individual also had a pathogenic somatic variant in BRCA2 (Schwartzberg and Kiedrowski. 2021. PubMed ID: 33868464). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-49047524-G-A) and has conflicting interpretations in ClinVar of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/237670/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000232184	SCV004844753	uncertain significance	Retinoblastoma	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 840 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 6/250396 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000232184	SCV005402280	uncertain significance	Retinoblastoma	2024-04-07	criteria provided, single submitter	clinical testing	The RB1 c.2518G>A (p.Gly840Arg) missense change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with retinoblastoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.