ClinVar Miner

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

dbSNP: rs747342068
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Total submissions: 23
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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

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