ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.584T>C (p.Ile195Thr) (rs760043106)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000437301 SCV000508608 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419621 SCV000508609 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429852 SCV000508610 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436603 SCV000508611 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418938 SCV000508612 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429211 SCV000508613 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439388 SCV000508614 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421751 SCV000508615 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428484 SCV000508616 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438726 SCV000508617 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421097 SCV000508618 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434805 SCV000508619 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441624 SCV000508620 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423911 SCV000508621 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434089 SCV000508622 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442071 SCV000508623 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000487386 SCV000568761 pathogenic not provided 2016-10-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.584T>C at the cDNA level, p.Ile195Thr (I195T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant was observed in an individual with a personal and family history of early-onset breast cancer, and occurred de novo in a patient with early-onset brain and colon cancers, with both cancers demonstrating loss of heterozygosity at the TP53 locus and microsatellite stability (Yamada 2009, Blanco 2010). TP53 Ile 195Thr is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). Other studies have also found this variant causes loss or reduction of transactivation activity for key reporter elements, rapid unfolding of the TP53 DNA binding domain, and is unable to suppress cell growth in a proliferation assay (Friedler 2003, Grochova 2008, Yamada 2009, Slovackova 2010).TP53 Ile195Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ile195Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. Despite the apparently heterozygous state observed for this TP53 variant, based on the reported personal/family history in this individual, the TP53 Ile195Thr variant is likely due to a somatic event in this individual's blood cells and not represented in the germline. Further testing on another tissue type, preferably fibroblasts, is recommended to determine whether this variant is present in this individual's germline or is the result of a somatically acquired event.One pathogenic germline variant in TP53 is indicative of 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, renal, 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 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). Radiation-induced second malignancies have been reported in individuals with Li-Fraumeni syndrome, suggesting that radiation may increase TP53 pathogenic variant carriers' risk for subsequent cancers within the radiation field (Bougeard 2015, Hisada 1998). Approximately 24% of LFS cases result from a de novo, rather than inherited, pathogenic variant in the TP53 gene (Chompret 2000). The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in TP53 (NCCN).
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785324 SCV000923892 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000198789 SCV000253849 pathogenic Li-Fraumeni syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 195 of the TP53 protein (p.Ile195Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. The frequency data for this variant (rs760043106) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported as a germline variant in individuals affected with breast cancer (PMID: 19930417, 26534844), and as de novo in an individual affected with glioblastoma and colon cancer (PMID: 19405127). In addition, this variant co-segregated with TP53-related disease in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 216077). Experimental studies have shown that this missense change causes functional inactivation of the TP53 protein (PMID: 19405127, 12700230, 17724467, 12826609). For these reasons, this variant has been classified as Pathogenic.

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