Submissions for variant NM_005732.4(RAD50):c.673G>A (p.Asp225Asn)

gnomAD frequency: 0.00002  dbSNP: rs587780159

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212905	SCV000149873	uncertain significance	not provided	2014-02-19	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.673G>A at the cDNA level, p.Asp225Asn (D225N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Asp225Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a negative polar amino acid is replaced with 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 are inconsistent with regard to the effect this variant may have on protein structure and function. At 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	RCV000115964	SCV000184165	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	The p.D225N variant (also known as c.673G>A), located in coding exon 5 of the RAD50 gene, results from a G to A substitution at nucleotide position 673. The aspartic acid at codon 225 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is 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	RCV000115964	SCV000548015	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	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 225 of the RAD50 protein (p.Asp225Asn). This variant is present in population databases (rs587780159, gnomAD 0.009%). 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: 128027). 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.
Sema4, Sema4	RCV002257411	SCV002538532	uncertain significance	Nijmegen breakage syndrome-like disorder	2021-05-01	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212905	SCV004220126	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000087 (3/34572 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.