ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.5C>T (p.Ser2Phe) (rs1554096631)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632227 SCV000753370 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 2 of the RAD50 protein (p.Ser2Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD50-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000632227 SCV000886457 likely benign Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter research The RAD50 variant designated as NM_005732.3:c.5C>T (p.Ser2Phe) is classified as likely benign. RAD50 has been associated with a small increase in breast cancer risk in some studies (Damiola et al, 2014, PMID: 24894818; Rebbeck et al 2011, PMID: 21799032), but found not to be associated with breast cancer in others (Couch et al. 2017, PMID: 28418444). In one observed family the RAD50 p.Ser2Phe variant was found not to segregate with breast cancer, as the variant was inherited paternally when close relatives with breast cancer were on the maternal side of the family. This indicates that the variant is less likely to cause breast cancer. In addition, this variant is not found in a key functional domain where other missense variants that are suspected to be associated with breast cancer have been identified (Damiola et al, 2014, PMID: 24894818). This variant is not listed in population databases. It is listed in the ClinVar database (Variation ID: 527368). Computer software programs have conflicting predictions on whether this variant is likely to be tolerated. The combined results are consistent with a classification of likely benign. This variant is not predicted to alter RAD50 function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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