ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1981C>T (rs137853294)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790652 SCV000227619 pathogenic not provided 2013-11-18 criteria provided, single submitter clinical testing
Invitae RCV000013962 SCV000551831 pathogenic Retinoblastoma 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 661 of the RB1 protein (p.Arg661Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137853294, ExAC 0.01%). This variant has been reported in many individuals affected with retinoblastoma (PMID: 12541220, 16269091, 23532519, 28575107, 24225018). It has been reported to segregate with retinoblastoma in multiple families (PMID: 1352883, 26925970, 17096365). While all tested affected individuals in the families had this variant, penetrance was reduced in comparison to truncating variants in RB1 seen in other families, with relatively mild phenotypic expression observed in some cases. Penetrance appears to be lower when this variant is inherited from the mother than from the father (PMID: 26925970). ClinVar contains an entry for this variant (Variation ID: 13087). Experimental studies have shown that this missense change has partial activity. It retains some ability to suppress retinoblastoma development, but is unstable with temperature-sensitive pocket protein-binding activity and defective in several aspects of cell cycle control (PMID: 18677112, 18682685, 10486322, 16449662, 15643604, 9632788). In summary, this variant causes partial loss of function of the RB1 protein and segregates with disease in multiple families, though with reduced penetrance. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492717 SCV000580810 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing <span style="font-family:arial,helvetica,sans-serif">The p.R661W pathogenic mutation with reduced penetrance (also known as c.1981C>T), located in coding exon 20 of the RB1 gene, results from a C to T substitution at nucleotide position 1981. The arginine at codon 661 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several RB families showing reduced penetrance where there are some individuals who are unaffected carriers; where some have unilateral RB; where some have bilateral RB; and some have regressed RB tumors (Onadim Z et al. Proc. Natl. Acad. Sci. U.S.A.. 1992 Jul;89:6177-81; Dommering CJ et al. J. Med. Genet. 2014 Jun;51:366-74; Eloy P et al. PLoS Genet. 2016 Feb;12:e1005888). In another study, the p.R661W pathogenic mutation accounted for approximately 3% (7/235) of unrelated retinoblastoma probands with germline RB1 mutations and approximately 13% (4/30) of germline mutations identified in probands with unilateral retinoblastoma (Richter S et al. Am. J. Hum. Genet. 2003 Feb;72:253-69). In addition, the p.R661W alteration has been shown to result in reduced, but not abolished, retinoblastoma protein activity (Whitaker LL et al. Mol. Cell. Biol. 1998 Jul;18:4032-42) and confers a decreased, albeit significant tumor risk (DiCiommo D et al. Semin. Cancer Biol. 2000 Aug;10:255-69). In a recent study including ten families with the p.R661W alteration, authors reported that if this alteration was maternally inherited the probability of being affected with RB was just under 10% whereas if this alteration was paternally inherited the probability of being affected with RB was almost 68%. They speculate that this parent-of-origin effect is due to maternal imprinting of an internal promoter which produces an alternative RB1 transcript and may contribute to the reduced penetrance of this mutation (Eloy P et al. PLoS Genet. 2016 Feb;12:e1005888; Kanber D et al. PLoS Genet. 2009 Dec;5:e1000790). Based on the supporting evidence, p.R661W is interpreted as a disease-causing mutation with reduced penetrance.
Fulgent Genetics,Fulgent Genetics RCV000763335 SCV000894012 pathogenic Osteosarcoma; Urinary bladder cancer; Small cell lung carcinoma; Retinoblastoma 2018-10-31 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000013962 SCV001478170 pathogenic Retinoblastoma 2020-12-15 criteria provided, single submitter research
OMIM RCV000013962 SCV000034209 pathogenic Retinoblastoma 1999-10-01 no assertion criteria provided literature only
Genetic Diagnostic Laboratory,University of Pennsylvania School of Medicine RCV000013962 SCV000087376 pathogenic Retinoblastoma 2013-09-16 no assertion criteria provided research
Genome Sciences Centre, British Columbia Cancer Agency RCV000510137 SCV000598654 likely pathogenic Vulvar adenocarcinoma of mammary gland type no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.