ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.494C>A (p.Pro165His) (rs104895044)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536422 SCV000628301 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-28 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 165 of the RAD50 protein (p.Pro165His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs104895044, ExAC 0.001%) but has not been reported in the literature in individuals with a RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 126996). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000536422 SCV001185168 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing The p.P165H variant (also known as c.494C>A), located in coding exon 4 of the RAD50 gene, results from a C to A substitution at nucleotide position 494. The proline at codon 165 is replaced by histidine, an amino acid with similar properties. This variant has been reported in an individual with immunoglobulin A deficiency (IgAD)/common variable immunodeficiency (CVID), who was also identified to carry a p.R327H alteration on the other RAD50 allele (Offer SM et al. PLoS ONE, 2010 Aug;5:e12260). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Harris Lab, University of Minnesota RCV000114862 SCV000148757 not provided not provided no assertion provided not provided

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