Submissions for variant NM_005732.4(RAD50):c.1958C>A (p.Ser653Ter)

gnomAD frequency: 0.00001  dbSNP: rs587781904

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130243	SCV000185086	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	The p.S653* pathogenic mutation (also known as c.1958C>A), located in coding exon 12 of the RAD50 gene, results from a C to A substitution at nucleotide position 1958. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration was observed in 1/1997 healthy controls and was not observed in 2000 breast cancer cases in one cohort (Thompson ER et al. J. Clin. Oncol. 2016 May;34(13):1455-9). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000130243	SCV000259716	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser653*) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). This variant is present in population databases (rs587781904, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 32338768). ClinVar contains an entry for this variant (Variation ID: 141646). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001535645	SCV002019627	pathogenic	Nijmegen breakage syndrome-like disorder	2019-04-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001535645	SCV004209730	pathogenic	Nijmegen breakage syndrome-like disorder	2021-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965074	SCV004794940	pathogenic	RAD50-related condition	2024-03-01	criteria provided, single submitter	clinical testing	The RAD50 c.1958C>A variant is predicted to result in premature protein termination (p.Ser653*). This variant has been observed in an individual with non-aggressive prostate, ovarian, breast cancer (Supplemental Table 1, Nguyen-Dumont et al. 2020. PubMed ID: 32338768; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Southey et al. 2021. PubMed ID: 34887416). This variant has been reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/141646/). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RAD50 are expected to be pathogenic. This variant is interpreted as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535645	SCV001749682	not provided	Nijmegen breakage syndrome-like disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.