Submissions for variant NM_005732.4(RAD50):c.2647C>T (p.Arg883Cys)

gnomAD frequency: 0.00032  dbSNP: rs138749920

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212919	SCV000149853	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)
Ambry Genetics	RCV000115944	SCV000183924	likely benign	Hereditary cancer-predisposing syndrome	2019-02-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000115944	SCV000254891	benign	Hereditary cancer-predisposing syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515220	SCV000611513	uncertain significance	Nijmegen breakage syndrome-like disorder	2017-05-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000515220	SCV002538484	likely benign	Nijmegen breakage syndrome-like disorder	2021-05-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469013	SCV002766304	benign	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.2647C>T (p.Arg883Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251140 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign n=1, likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212919	SCV001552795	likely benign	not provided		no assertion criteria provided	clinical testing	The RAD50 p.Arg883Cys variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs138749920) as Uncertain Significance and likely Benign, ClinVar (Reported as Likely Benign by Ambry in 2018, Likely benign by Invitae in 2017, Uncertain significance by Fulgent in 2017, Uncertain significance by GeneDx in 2014), Clinvitae (Likely benign [Invitae], Uncertain significance [ClinVar]), databases. The variant was not identified in Cosmic or LOVD 3.0, databases. The variant was identified in control databases in 152 of 282540 chromosomes (1 homozygous) at a frequency of 0.000538 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 82 of 10366 chromosomes (freq: 0.00791), South Asian in 29 of 30584 chromosomes (freq: 0.000948), Other in 5 of 7206 chromosomes (freq: 0.000694), Latino in 12 of 35384 chromosomes (freq: 0.000339), European (non-Finnish) in 21 of 128990 chromosomes (freq: 0.000163), African in 2 of 24956 chromosomes (freq: 0.00008), East Asian in 1 of 19950 chromosomes (freq: 0.00005), while the variant was not observed in the and European (Finnish) populations. The p.Arg883C variant was reported as a variant of uncertain significance in a population of 278 BRCA1/2 negative patients with early onset breast cancer who received sequencing of 22 cancer susceptibility genes (Maxwell_2015_PMID: 25503501). The p.Arg883Cys variant was also reported as a variant of uncertain significance in a population of 1040 cancer patients who received germline analysis of 76 cancer predisposition genes (Mandelker_2017_PMID: 23555315). The p.Arg883Cys variant was also identified through genotyping 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls (Haiman_2013_PMID: 23555315). The p.Arg883Cys variant was not found to be significantly associated with breast or prostate cancer (Haiman_2013_PMID: 23555315). The p.Arg883 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the R variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References Haiman CA et al. Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. PLoS Genet. 2013 Mar;9(3):e1003419. doi: 0.1371/journal.pgen.1003419. Epub 2013 Mar 28. PMID: 23555315 Mandelker D et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137. PMID: 28873162 Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8. doi: 10.1038/gim.2014.176. Epub 2014 Dec 11. PubMed PMID:25503501
GenomeConnect - Invitae Patient Insights Network	RCV000515220	SCV004228537	not provided	Nijmegen breakage syndrome-like disorder		no assertion provided	phenotyping only	Variant interpreted as Benign and reported on 06-27-2019 by Lab 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.