ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2299G>A (p.Asp767Asn)

gnomAD frequency: 0.00004  dbSNP: rs587782282
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131143 SCV000186081 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing The p.D767N variant (also known as c.2299G>A), located in coding exon 14 of the RAD50 gene, results from a G to A substitution at nucleotide position 2299. The aspartic acid at codon 767 is replaced by asparagine, an amino acid with highly similar properties. In one study, this alteration was identified in 3/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers. (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). In another study, this alteration was detected in the germline of 1/50 adolescent or young adult patients with cutaneous melanoma (Wilmott JS et al. Int. J. Cancer, 2019 03;144:1049-1060). This amino acid position is not well conserved in 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 RCV000131143 SCV000254886 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 767 of the RAD50 protein (p.Asp767Asn). This variant is present in population databases (rs587782282, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 142173). 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.

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