ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln) (rs146370443)

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Total submissions: 9
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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 In silico models in agreement (benign);Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV000115926 SCV000254872 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 365 of the RAD50 protein (p.Arg365Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs146370443, ExAC 0.06%). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26689913, 24894818, 30441849, 30306255). 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; Align-GVGD: Class C0. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 and 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 2020-05-14 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 Hereditary Breast And Ovarian Cancer Syndrome as well as other types of cancer (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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four 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.
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.

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