Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001024540 | SCV001186572 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-01-29 | criteria provided, single submitter | clinical testing | The p.H193Q variant (also known as c.579T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 579. The histidine at codon 193 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified as de novo in a patient meeting Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This alteration has been reported as a somatic mutation 3 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). Although this specific variant has not been reported in the literature as a germline alteration, two other alterations at this same codon (p.H193Y, p.H193R) have been reported as germline alterations in cases of Li Fraumeni syndrome (Petitjean A et al. IARC TP53 database [version R18, April 2016]. Hum Mutat. 2007 Jun;28(6):622-9; Frebourg T, Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |