Submissions for variant NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln)

gnomAD frequency: 0.00026  dbSNP: rs146370443

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212907	SCV000149835	uncertain significance	not provided	2021-05-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and ovarian cancer (Lu 2015, Fanale 2020); This variant is associated with the following publications: (PMID: 31159747, 32854451, 30441849, 26689913)
Ambry Genetics	RCV000115926	SCV000183886	likely benign	Hereditary cancer-predisposing syndrome	2019-02-01	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	RCV000115926	SCV000254872	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000515281	SCV000611508	uncertain significance	Nijmegen breakage syndrome-like disorder	2017-05-23	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115926	SCV000822142	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030501	SCV001193701	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199877	SCV001370628	likely benign	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.1094G>A (p.Arg365Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251162 control chromosomes. The observed variant frequency is approximately 7.33 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. c.1094G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome as well as other types of cancer (example, Lu_2015, Bonache_2018, Damiola_2014, Koczkowska_2018, Parachoniak_2017, Tsaousis_2019, Young_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, six classified the variant as a VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212907	SCV002009653	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153375	SCV003843834	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003242983	SCV003936828	uncertain significance	Familial cancer of breast	2023-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 365 of the RAD50 protein (p.Arg365Gln). This variant is present in population databases (rs146370443, gnomAD 0.06%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 24894818, 26689913, 30306255, 30441849). ClinVar contains an entry for this variant (Variation ID: 127990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003407501	SCV004115384	uncertain significance	RAD50-related condition	2023-07-08	criteria provided, single submitter	clinical testing	The RAD50 c.1094G>A variant is predicted to result in the amino acid substitution p.Arg365Gln. This variant has been reported as a variant of uncertain significance in patients tested using a panel of genes for hereditary cancer syndrome (Table S5, Tsaousis et al. 2019. PubMed ID 3115974), as well as in patients with breast or ovarian cancer (Table S9, Bonache et al. 2018. PubMed ID: 30306255; Damiola et al. 2014. PubMed ID 24894818; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S12, Lu et al. 2015. PubMed ID 26689913; Table 4, Fanale et al. 2020. PubMed ID 32854451). It has also been reported in a metastatic liver biopsy specimen (Table S2, Parachoniak et al. 2017. PubMed ID: 28550065). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131924421-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127990/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212907	SCV004219269	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0011 (38/33046 chromosomes in the 'Other non-Finnish European' subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals or families with breast/ovarian cancer (PMIDs: 32854451 (2020), 31159747 (2019), 30306255 (2018), 28550065 (2017), 24894818 (2014)), ovarian cancer alone (PMIDs: 30441849 (2018), 26689913 (2015)), and colorectal cancer (PMID: 33563768 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212907	SCV001552388	likely benign	not provided		no assertion criteria provided	clinical testing	The RAD50 p.Arg365Gln variant was identified in 5 of 10694 proband chromosomes (frequency: 0.000468) from individuals or families with breast and ovarian cancer and was not identified in 1121 control chromosomes from healthy individuals (Damiola_2014_24894818; Lu_2015_PMID: 26689913). The variant was also identified in dbSNP (ID: rs146370443), ClinVar (conflicting interpretations of pathogenicity: one likely benign submission by Ambry Genetics and four VUS submissions by GeneDx, Invitae, Fulgent Genetics and GeneKor MSA; associated conditions are Nijmegen breakage syndrome-like disorder and Hereditary cancer-predisposing syndrome. The variant was identified in control databases in 122 of 282506 chromosomes at a frequency of 0.000432 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was not identified in the Cosmic and LOVD 3.0 databases. The variant was observed in the following populations: European (non-Finnish) in 79 of 128920 chromosomes (freq: 0.000613), East Asian in 12 of 19952 chromosomes (freq: 0.000601), South Asian in 16 of 30592 chromosomes (freq: 0.000523), Other in 3 of 7210 chromosomes (freq: 0.000416), Latino in 8 of 35398 chromosomes (freq: 0.000226), European (Finnish) in 4 of 25110 chromosomes (freq: 0.000159), while the variant was not observed in the African, and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg365 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535589	SCV001749589	not provided	Familial cancer of breast; Nijmegen breakage syndrome-like disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-11-2020 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.