ClinVar Miner

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

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198789 SCV000253849 pathogenic Li-Fraumeni syndrome 2020-02-03 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.
GeneDx RCV000487386 SCV000568761 pathogenic not provided 2020-03-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Yamada 2009, Slovackova 2010, Kotler 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17724467, 27059324, 10567903, 30720243, 15510160, 12826609, 12700230, 26585234, 19930417, 20505364, 19405127, 21484931, 22784333, 29979965, 12124823, 12509970, 16322298, 7732013, 11238194, 20118236, 29324801, 30840781, 27501770, 29625052)
Ambry Genetics RCV001024600 SCV001186639 pathogenic Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The p.I195T pathogenic mutation (also known as c.584T>C), located in coding exon 5 of the TP53 gene, results from a T to C substitution at nucleotide position 584. The isoleucine at codon 195 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a male patient diagnosed with glioblastoma and colon cancer at age 21; his unaffected parents both tested negative for the alteration (Yamada H et al. Int. J. Cancer 2009 Aug;125:973-6). This variant was also observed in a family with early onset breast cancer, bone cancer and glioblastoma (Bouaoun L et al. IARC TP53 database [version R19, August 2018]. Hum. Mutat. 2016 Sep;37:865-76); and in patients with early-onset breast cancer (Blanco A et al. Clin. Genet. 2010 Feb;77:193-6; Stoltze U et al. PLoS ONE 2018 Jan;13:e0190050). 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 has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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.
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 Breast neoplasm 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
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785324 SCV000923892 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
CZECANCA consortium RCV001271054 SCV001451873 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided case-control
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000487386 SCV001906056 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000487386 SCV001959237 pathogenic not provided no assertion criteria provided clinical testing

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