Submissions for variant NM_000546.6(TP53):c.584T>A (p.Ile195Asn)

dbSNP: rs760043106

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692717	SCV000820555	uncertain significance	Li-Fraumeni syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 195 of the TP53 protein (p.Ile195Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rhabdomyosarcoma and ovarian cancer (PMID: 16337994, 27714481). ClinVar contains an entry for this variant (Variation ID: 376618). 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: 12826609). 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.
Ambry Genetics	RCV001024599	SCV001186638	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	clinical testing	The p.I195N pathogenic mutation (also known as c.584T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 584. The isoleucine at codon 195 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported in an individual with rhabdomyosarcoma (Andrade RC et al. Fam Cancer, 2017 04;16:243-248). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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). Another alteration at the same codon, p.I195T (c.584T>C), has been 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). The p.I195N 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV001024599	SCV002582053	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289528	SCV002582391	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000440578	SCV000508640	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422932	SCV000508641	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433212	SCV000508642	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442006	SCV000508643	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425779	SCV000508644	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432578	SCV000508645	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444669	SCV000508646	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424894	SCV000508647	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435160	SCV000508648	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417492	SCV000508649	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427719	SCV000508650	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437965	SCV000508651	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420311	SCV000508652	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430554	SCV000508653	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440765	SCV000508654	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419606	SCV000508655	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785514	SCV000924086	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research