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

dbSNP: rs587782197

Total submissions: 7

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