Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000223280 | SCV000274860 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-04-02 | criteria provided, single submitter | clinical testing | The p.A491T variant (also known as c.1471G>A), located in coding exon 10 of the RAD50 gene, results from a G to A substitution at nucleotide position 1471. The alanine at codon 491 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 40000 alleles tested) in our clinical cohort. 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 p.A491T remains unclear. |
| Invitae | RCV000223280 | SCV002284586 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-11-02 | criteria provided, single submitter | clinical testing | 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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 231112). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 491 of the RAD50 protein (p.Ala491Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. |