Submissions for variant NM_000546.6(TP53):c.394A>G (p.Lys132Glu)

dbSNP: rs747342068

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000468362	SCV000545306	pathogenic	Li-Fraumeni syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 132 of the TP53 protein (p.Lys132Glu). This variant is present in population databases (rs747342068, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of TP53-related conditions (PMID: 9157982, 28135145; Invitae). ClinVar contains an entry for this variant (Variation ID: 376626). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 9157982, 12826609, 21343334, 29979965, 30224644). This variant disrupts the p.Lys132 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 29753700, 29979965, 30224644; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000562533	SCV000664399	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.K132E pathogenic mutation (also known as c.394A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 394. The lysine at codon 132 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in an individual diagnosed with rhabdomyosarcoma at age 2 and osteosarcoma at age 11 and have two relatives in two generations diagnosed with breast cancer (IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. 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 variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Chappuis PO et al. Int. J. Cancer 1999 Dec; 84(6):587-93; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This amino acid position is highly conserved in 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253548	SCV001429318	pathogenic	Li-Fraumeni syndrome 1	2020-09-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000562533	SCV002582397	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001253548	SCV002583059	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017609	SCV004848162	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing	The p.Lys132Glu variant in TP53 has been reported in 1 individual with Li-Fraumeni syndrome and a 34 year old unaffected brother (Goi 1997). This variant has been identified in 1/9846 Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/; dbSNP ID rs747342068) . It is reported in ClinVar (Variation ID: 376626) with conflicting interpretations. Computational prediction tools and in vitro functional studies suggest that the p.Lys132Glu variant may impact protein function (Goi 1997, Monti 2007, Monti 2011). However, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Lys132Glu variant is uncertain. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3.
Myriad Genetics, Inc.	RCV001253548	SCV004931942	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: 9157982, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9157982].
Database of Curated Mutations (DoCM)	RCV000433855	SCV000508748	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442199	SCV000508749	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426379	SCV000508750	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436180	SCV000508751	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444903	SCV000508752	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425237	SCV000508753	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435981	SCV000508754	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417874	SCV000508755	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428580	SCV000508756	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434893	SCV000508757	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417803	SCV000508758	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431096	SCV000508759	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441816	SCV000508760	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423644	SCV000508761	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430828	SCV000508762	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440656	SCV000508763	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only