Submissions for variant NM_000546.5(TP53):c.713G>T (p.Cys238Phe) (rs730882005)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	Uterine cervical neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417498	SCV000507713	likely pathogenic	Neoplasm of the breast	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	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	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Invitae	RCV000473420	SCV000545304	pathogenic	Li-Fraumeni syndrome	2018-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with phenylalanine at codon 238 of the TP53 protein (p.Cys238Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with a TP53-related disease, but has been reported as a somatic variant in various human cancers (PMID: 16337994, 20407015, 24590827, 21115975, 26781615, 27179933, 20878954). ClinVar contains an entry for this variant (Variation ID: 376574). Experimental studies have shown that this variant results in significantly decreased transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 20407015, 25691460). In addition, this variant has been classified as a high-risk mutation associated with decreased drug sensitivity in vitro and in vivo (PMID: 25691460, 25504633, 25634208). The cysteine residue at codon 238 is involved in coordinating a zinc ion in the DNA-binding domain of the TP53 protein (PMID: 8023157, 20407015, 22866089). Different amino acid changes at the same codon (p.Cys238Trp and p.Cys238Tyr) have been observed in individuals with a TP53-related disease and classified as pathogenic variants in the Invitae database, indicating that cysteine 238 is critical for proper protein function. For these reasons, this variant has been classified as Pathogenic.