Submissions for variant NM_000546.6(TP53):c.374C>A (p.Thr125Lys)

dbSNP: rs786201057

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197507	SCV000254630	pathogenic	Li-Fraumeni syndrome	2021-07-07	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr125 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25503501, 26845104, 26014290, 18511570, 16508005, 27533082, 17401428, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609). This variant has been observed to be de novo in an individual affected with clinical features of Li-Fraumeni syndrome (PMID: 29070607). ClinVar contains an entry for this variant (Variation ID: 216465). This sequence change replaces threonine with lysine at codon 125 of the TP53 protein (p.Thr125Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine.
Ambry Genetics	RCV003165469	SCV003911999	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The p.T125K variant (also known as c.374C>A), located in coding exon 3 of the TP53 gene, results from a C to A substitution at nucleotide position 374. The threonine at codon 125 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as a de novo finding in an individual with a personal history of colorectal cancer diagnosed at age 24, and bilateral breast cancers diagnosed at ages 31 and 34 (Renaux-Petel M et al. J Med Genet, 2018 03;55:173-180). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration has also been reported in an individual with a pulmonary sarcomatoid carcinoma (Li YF et al. Front Genet, 2022 Jul;13:949989). 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 no 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.T125R (c.374C>G), has been reported in several families meeting clinical criteria for Li Fraumeni syndrome (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91; Waszak SM et al. Lancet Oncol. 2018 06;19:785-798; Li JY et al. Int J Cancer. 2019 01;144:281-289). The p.T125K 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 majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM)	RCV000430953	SCV000509841	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441651	SCV000509842	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423507	SCV000509843	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430716	SCV000509844	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438784	SCV000509845	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421753	SCV000509846	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431571	SCV000509847	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443320	SCV000509848	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422366	SCV000509849	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433115	SCV000509850	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443241	SCV000509851	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425663	SCV000509852	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433745	SCV000509853	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442723	SCV000509854	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426240	SCV000509855	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436943	SCV000509856	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420607	SCV000509857	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427801	SCV000509858	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437594	SCV000509859	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420405	SCV000509860	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only