ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.434T>A (p.Leu145Gln) (rs587782197)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565971 SCV000664434 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-28 criteria provided, single submitter clinical testing The p.L145Q variant (also known as c.434T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 434. The leucine at codon 145 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 20 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(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is not well 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.
Color Health, Inc RCV000565971 SCV000904366 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-28 criteria provided, single submitter clinical testing This missense variant replaces leucine with glutamine at codon 145 of the DNA binding domain of the TP53 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant impairs Tp53 protein function. The mutant protein has shown to be non-functional in yeast transactivation assays (IARC database and PMID: 12826609), in human cell proliferation assay (PMID: 29979965) and in human cell growth suppression assay (PMID: 30224644). This variant has been reported in an individual affected with breast cancer whose family history met Li-Fraumeni syndrome Chompret criteria (PMID: 30980208). This variant has also been observed to segregate with disease in three individuals from a family affected with Li-Fraumeni syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785310 SCV000923878 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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