Submissions for variant NM_005732.4(RAD50):c.2563G>T (p.Asp855Tyr)

gnomAD frequency: 0.00001  dbSNP: rs144911328

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130353	SCV000185204	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	The p.D855Y variant (also known as c.2563G>T), located in coding exon 16 of the RAD50 gene, results from a G to T substitution at nucleotide position 2563. The aspartic acid at codon 855 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was detected in a cohort of 690 patients with myeloid malignancy (Li ST et al. Leukemia, 2020 Jun;34:1675-1678). 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.
Invitae	RCV000130353	SCV000548039	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 855 of the RAD50 protein (p.Asp855Tyr). This variant is present in population databases (rs144911328, gnomAD 0.02%). 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: 141730). 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 expected to disrupt RAD50 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000585129	SCV000693187	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000585129	SCV002009650	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing