ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.358A>G (p.Lys120Glu) (rs121912658)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129457 SCV000184227 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s)
GeneDx RCV000213049 SCV000211797 pathogenic not provided 2014-05-05 criteria provided, single submitter clinical testing This variant is denoted TP53 c.358A>G at the cDNA level, p.Lys120Glu (K120E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG) in exon 4. Lys120 acetylation is necessary for proper TP53 function (Dai 2011, Rokudai 2013). Specifically, this mutation has been demonstrated to render cells defective with respect to both cell cycle arrest and apoptosis (Sykes 2006, Sykes 2009). TP53 Lys120Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Lys120Glu alters a position that is highly conserved across species and is located in a DNA binding domain (Dai 2011). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on current information, we consider this mutation to be pathogenic. Mosaicism for TP53 mutations has been reported in at least three patients, all of whom had cancer themselves and none of whom had a family history significant for Li Fraumeni syndrome (Prochazkova 2009, Walsh 2011, Mitchell 2013). One pathogenic germline mutation in TP53 causes Li-Fraumeni syndrome (LFS), an autosomal dominant condition associated with a high risk for a broad range of childhood- and adult-onset cancers. The following core cancer types account for 70%-77% of LFS-associated tumors (in order of frequency): breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, and adrenocortical carcinoma (Gonzalez 2009, Olivier 2003, Ruijs 2010). Other types of cancer that have been reported to be associated with LFS include ovarian, gastrointestinal, pancreatic, genitourinary, skin, thyroid and lung cancers as well as leukemia, lymphoma, and neuroblastomas. Age-related and sex-specific cancer risks have been reported. According to one study, the overall risks for males with LFS to develop cancer by ages 16, 45, and 85 are estimated to be 19%, 41%, and 73%, respectively, whereas the risks for females are estimated to be 12%, 84%, and 100%, respectively (Chompret 2000). The higher penetrance in females is due to the high incidence of breast cancer, accounting for 80% of the cancers in the age group of 16 to 45 years (Chompret 2000). The majority of LFS-associated breast cancers are HER2/neu positive ductal carcinomas (Melhem-Bertrandt 2012). The most common types of sarcomas in LFS are rhabdomyosarcomas before age 5 and osteosarcomas at any age (Ognjanovic 2012). LFS is associated with many types of brain tumors including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas, and they can occur in childhood or adulthood (Olivier 2003). Individuals with LFS who have been diagnosed with cancer have up to a 57% risk of a second primary cancer within 30 years of the first diagnosis and up to a 38% risk of a third primary diagnosis (Hisada 1998). Several studies have demonstrated that subsequent tumors often develop in the radiation field of the previously treated cancer (Chompret 2000, Hisada 1998). Approximately 24% of LFS cases result from a de novo, rather than inherited, mutation in the TP53 gene (Chompret 2000). This variant has been seen apparently mosaic. The variant is found in BR-OV-HEREDIC panel(s).
Invitae RCV000696142 SCV000824690 uncertain significance Li-Fraumeni syndrome 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 120 of the TP53 protein (p.Lys120Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported as a germline variant in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 141098). Experimental studies have shown that this missense change abolishes transactivation capacity of TP53 and causes defects in both cell cycle arrest and apoptosis (PMID: 12826609, 12909720, 15138567, 17189187). 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.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785522 SCV000924094 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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