ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.434T>A (p.Leu145Gln)

dbSNP: rs587782197
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565971 SCV000664434 pathogenic Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing The p.L145Q pathogenic mutation (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 variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health 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.
GeneDx RCV001537369 SCV001754244 likely pathogenic not provided 2021-01-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity, and dominant-negative effect (Kato 2003, Kotler 2018, Giacomelli 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with breast cancer who reportedly met Chompret criteria, although family history details were not provided (Bernstein-Molho 2019); This variant is associated with the following publications: (PMID: 30726928, 30224644, 30980208, 29979965, 10713666, 21561095, 30808373)
Labcorp Genetics (formerly Invitae), Labcorp RCV003621548 SCV004535373 uncertain significance Li-Fraumeni syndrome 2024-04-16 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 145 of the TP53 protein (p.Leu145Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 30980208). ClinVar contains an entry for this variant (Variation ID: 480760). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects 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.
All of Us Research Program, National Institutes of Health RCV003621548 SCV004823808 likely pathogenic Li-Fraumeni syndrome 2023-10-09 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.
Myriad Genetics, Inc. RCV004024460 SCV004932989 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785310 SCV000923878 likely pathogenic Ovarian neoplasm 2018-12-01 no assertion criteria provided research

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