ClinVar Miner

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

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Total submissions: 18
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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.

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