Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001011875 | SCV001172253 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-06-20 | criteria provided, single submitter | clinical testing | The p.F505S variant (also known as c.1514T>C), located in coding exon 9 of the ATM gene, results from a T to C substitution at nucleotide position 1514. The phenylalanine at codon 505 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was identified in cis with ATM c.1547T>C (p.L516S) in four children from a consanguineous Arabic family with a mild presentation of Ataxia Telangiectasia, each of whose parents were found to be heterozygous for this haplotype. This same report also found that cells from these children showed reduced, but not absent, ATM protein expression as well as reduced and delayed phosphorylation of KAP1 (an ATM substrate) after neocarzinostatin-induced DNA damage (Bielorai B et al. Pediatr Hematol Oncol, 2013 Sep;30:574-82).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV002550771 | SCV003440587 | uncertain significance | Ataxia-telangiectasia syndrome | 2022-09-10 | 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 819371). This missense change has been observed in individual(s) with clinical features of autosomal recessive ATM-related conditions and/or malignant peritoneal mesothelioma (PMID: 23509889, 30124550). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 505 of the ATM protein (p.Phe505Ser). |