Submissions for variant NM_000546.6(TP53):c.584T>C (p.Ile195Thr)

dbSNP: rs760043106

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198789	SCV000253849	pathogenic	Li-Fraumeni syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the TP53 protein (p.Ile195Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 19405127; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216077). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12700230, 12826609, 19405127, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000487386	SCV000568761	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Yamada et al., 2009; Slovackova et al., 2010; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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, 12124823, 19405127, 27714481, 26534844, 29324801, 12826609, 20505364, 29979965, 15510160, 19930417, 27501770, 12700230, 26585234, 21484931, 22784333, 20118236, 29625052, 30840781, 11238194, 12509970, 7732013, 16322298)
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.
Genome-Nilou Lab	RCV001024600	SCV002582486	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288812	SCV002583147	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research	RCV000421097	SCV003806326	uncertain significance	Lung adenocarcinoma	2022-06-06	criteria provided, single submitter	research
Baylor Genetics	RCV003474953	SCV004204268	pathogenic	Adrenocortical carcinoma, hereditary	2022-11-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288812	SCV004932961	pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19405127, 19930417, 27501770]. Functional studies indicate this variant impacts protein function [PMID: 19405127, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
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	B-cell 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	Gastric adenocarcinoma	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, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487386	SCV001959237	pathogenic	not provided		no assertion criteria provided	clinical testing