Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164060 | SCV000214668 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-28 | criteria provided, single submitter | clinical testing | The p.N152Y variant (also known as c.454A>T), located in coding exon 4 of the RAD50 gene, results from an A to T substitution at nucleotide position 454. The asparagine at codon 152 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified in 1/1824 patients diagnosed with triple negative breast cancer and unselected for family history; this cohort underwent panel testing for 17 cancer predisposition genes (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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 | RCV000164060 | SCV000548084 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 152 of the RAD50 protein (p.Asn152Tyr). This variant is present in population databases (rs772250365, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 184750). 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%. 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. |