Submissions for variant NM_000546.6(TP53):c.408A>C (p.Gln136His)

dbSNP: rs758781593

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165874	SCV000216624	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The p.Q136H variant (also known as c.408A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 408. The glutamine at codon 136 is replaced by histidine, an amino acid with highly similar properties. This variant has also been identified as a germline alteration in a patient with prostate cancer (Zheng L, Hum. Mutat. 2006 Oct; 27(10):1062-3). This alteration is located in the functionally critical DNA binding domain and is reported to have a loss of transactivation capacity in yeast based functional studies (IARC TP53 database; Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration has no dominant negative effect and 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229644	SCV000285194	uncertain significance	Li-Fraumeni syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 136 of the TP53 protein (p.Gln136His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer and clinical features of Li-Fraumeni syndrome (LFS) (PMID: 16941491; internal data). ClinVar contains an entry for this variant (Variation ID: 186301). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Genome-Nilou Lab	RCV000165874	SCV002582087	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288752	SCV002582650	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003332133	SCV004040184	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mixed results: non-functional transactivation, but retained growth suppression abilities and no dominant negative effect (Kato et al., 2003; Giacomelli et al., 2018; Kotler et al., 2018); This variant is associated with the following publications: (PMID: 12576437, 15510160, 30840781, 29979965, 12826609, 35286522, 16941491, 28160562, 30224644)