Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001218247 | SCV001390121 | pathogenic | Li-Fraumeni syndrome | 2023-09-13 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 178 of the TP53 protein (p.His178Gln). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His178 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 21345075, 22829111, 24814347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 947223). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 24382691; Invitae). |
| Ambry Genetics | RCV002348728 | SCV002645060 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-25 | criteria provided, single submitter | clinical testing | The p.H178Q variant (also known as c.534C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 534. The histidine at codon 178 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in the literature in a child affected by rhabdomyosarcoma (Hettmer S et al. Cancer, 2014 Apr;120:1068-75). In addition, this alteration has been detected in a family meeting Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals but not in all 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. |