ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212907 SCV000149835 uncertain significance not provided 2014-01-20 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.1094G>A at the cDNA level, p.Arg365Gln (R365Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg365Gln was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics RCV000115926 SCV000183886 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000115926 SCV000254872 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-23 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 affected with breast cancer (PMID: 24894818) and ovarian cancer (PMID: 26689913). 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
Integrated Genetics/Laboratory Corporation of America 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.

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