Submissions for variant NM_000546.6(TP53):c.395A>C (p.Lys132Thr)

dbSNP: rs1057519996

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003621532	SCV004490884	uncertain significance	Li-Fraumeni syndrome	2022-12-05	criteria provided, single submitter	clinical testing	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. 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: 376627). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 132 of the TP53 protein (p.Lys132Thr).
Ambry Genetics	RCV004022225	SCV005036121	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-06	criteria provided, single submitter	clinical testing	The p.K132T pathogenic mutation (also known as c.395A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 395. The lysine at codon 132 is replaced by threonine, an amino acid with similar properties. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). This amino acid position is highly conserved in available vertebrate species. This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Two other alterations at the same codon, p.K132R (c.395A>G) and p.K132E (c.394A>G), have demonstrated abnormal protein function in functional assays and the p.K132E alteration has been described in a family meeting Li Fraumeni syndrome clinical criteria (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Database of Curated Mutations (DoCM)	RCV000423393	SCV000508764	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433243	SCV000508765	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443063	SCV000508766	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422403	SCV000508767	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433123	SCV000508768	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442106	SCV000508769	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425633	SCV000508770	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435461	SCV000508771	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442467	SCV000508772	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424547	SCV000508773	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437910	SCV000508774	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420694	SCV000508775	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427017	SCV000508776	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437675	SCV000508777	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419605	SCV000508778	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430299	SCV000508779	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only