ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2173C>T (p.Arg725Trp) (rs369560280)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131653 SCV000186680 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing The p.R725W variant (also known as c.2173C>T), located in coding exon 13 of the RAD50 gene, results from a C to T substitution at nucleotide position 2173. The arginine at codon 725 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this alteration was observed in 3/158 Hispanic individuals who were diagnosed with breast cancer before the age of 45, and was not seen in any controls matched for age and ethnicity (<span style="background-color:initial">Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This alteration was also detected in a cohort of 327 Mexican patients with personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel). 2018 Sep;10).This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000131653 SCV000289031 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 725 of the RAD50 protein (p.Arg725Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs369560280, ExAC 0.1%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24894818, 30262796). ClinVar contains an entry for this variant (Variation ID: 142505). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780661 SCV000918119 likely benign not specified 2018-01-02 criteria provided, single submitter clinical testing Variant summary: The RAD50 c.2173C>T (p.Arg725Trp) variant involves the alteration of a conserved nucleotide that is located in the RAD50, zinc hook domain (InterPro). 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 55/275042 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.001541 (53/34384). This frequency is about 25 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been cited in the literature, though it is unclear whether it was identified in breast cancer cases or control individuals (Damiola_2014; Young_2016). Two clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. Taken together, this variant is classified as likely benign.

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