Submissions for variant NM_000546.6(TP53):c.713G>T (p.Cys238Phe)

dbSNP: rs730882005

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473420	SCV000545304	pathogenic	Li-Fraumeni syndrome	2023-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys238 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 20407015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20407015, 25504633, 25634208, 25691460, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376574). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 16337994, 20407015, 20878954, 21115975, 24590827, 26781615, 27179933). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 238 of the TP53 protein (p.Cys238Phe).
Ambry Genetics	RCV002365459	SCV002665492	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	The p.C238F pathogenic mutation (also known as c.713G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 713. The cysteine at codon 238 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). Multiple other alterations at the same codon, p.C238Y, p.C238S, p.C238R and p.C238G, have been been detected in families meeting LFS criteria (Balmaña J, Med Clin (Barc) 2002 Oct; 119(13):497-9; Krutilkova V et al. Eur J Cancer, 2005 Jul;41:1597-603;Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9); Ambry internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000473420	SCV003845014	likely pathogenic	Li-Fraumeni syndrome	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.713G>T (p.Cys238Phe) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615), affecting a Zn2+ binding site (UniProt) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.713G>T has been reported in the literature in individuals affected with TP53-related conditions (e.g., Schwartz_2021, Patel_1995, Kim_2018). Several publications report experimental evidence evaluating an impact on protein function, classifying the protein variant as non-functional in a transactivation assay and finding the variant displayed <1% transcriptional activity in yeast (e.g., Jordan_2010, Giacomelli_2018, Kotler_2018). Two ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Additionally, missense variants impacting the same amino acid residue, C238, have been reported as pathogenic in ClinVar and associated with Li-Fraumeni in HGMD (e.g., p.C238R, p.C238G, p.C238S, p.C238Y, p.C238W). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004022207	SCV004933339	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25691460, 7791795]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000439349	SCV000507701	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422481	SCV000507702	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432745	SCV000507703	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440369	SCV000507704	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422719	SCV000507705	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433862	SCV000507706	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442469	SCV000507707	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427235	SCV000507708	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433989	SCV000507709	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444988	SCV000507710	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427531	SCV000507711	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435149	SCV000507712	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417498	SCV000507713	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425072	SCV000507714	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435343	SCV000507715	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418555	SCV000507716	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428817	SCV000507717	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only