Submissions for variant NM_000546.6(TP53):c.374C>T (p.Thr125Met)

gnomAD frequency: 0.00001  dbSNP: rs786201057

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162461	SCV000212818	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The p.T125M variant (also known as c.374C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 374. The threonine at codon 125 is replaced by methionine, an amino acid with similar 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). However, studies conducted in human cell lines indicate this alteration is proficient 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). This variant has been reported in multiple individuals with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836) as well as in two individuals with childhood-onset adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52). 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). In addition, several functional studies indicate that p.T125R is deleterious (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; Menendez D et al. Mol. Cell. Biol. 2006 Mar;26:2297-308). The p.T125M 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000162461	SCV000266132	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000237013	SCV000292695	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate significantly reduced transactivation in some studies but higher activity in others, and no loss of growth suppression activity (Kato et al., 2003, Perez et al., 2016, Giacomelli et al., 2018, Kotler et al., 2018, Pinto et al., 2021); Published functional studies investigating splicing found a low level of aberrant transcripts also present in wildtype controls, suggesting they may be naturally occurring isoforms (Pinto et al., 2021); Although this variant has been observed in individuals with a personal history of LFS-related cancers, such as adrenocortical carcinoma or early-onset breast cancer, it has not to our knowledge been reported in a family meeting classic LFS criteria or as a de novo variant. This variant has also been reported in unaffected adults and others whose histories are not consistent with LFS. (Bougeard et al., 2015, Maxwell et al., 2015, Shirts et al., 2016, de Andrade et al., 2017, Hu et al., 2018, Weber-Lasalle et al., 2018, Lu et al., 2019, Weitzel et al., 2019, Pinto et al., 2021).; This variant is associated with the following publications: (PMID: 27237367, 19046423, 21118481, 26849095, 26845104, 14559903, 20436704, 25503501, 10761705, 27998968, 27022024, 28369373, 26014290, 29319699, 12826609, 29079180, 30216591, 28861920, 30352134, 29922827, 30128536, 28472496, 30720243, 30840781, 31016814, 31206626, 31105275, 29979965, 30224644, 34675114, 15510160, 31794323, 35664418, 35426462)
Invitae	RCV000457119	SCV000545359	pathogenic	Li-Fraumeni syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the TP53 protein (p.Thr125Met). This variant is present in population databases (rs786201057, gnomAD 0.01%). This missense change has been observed in individuals with adrenocortical carcinoma, breast cancer, and/or Li-Fraumeni-associated cancers (PMID: 25503501, 26014290, 26845104; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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: 12826609, 16508005; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000576336	SCV000677813	likely pathogenic	Li-Fraumeni syndrome 1	2016-10-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162461	SCV000691590	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. One RNA study showed use of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373; DOI:10.7759/cureus.24602) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536, 34675114), ovarian cancer (PMID: 30216591), and bladder urothelial carcinoma (PMID: 34240179). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000237013	SCV001134868	likely pathogenic	not provided	2019-02-12	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Sema4, Sema4	RCV000162461	SCV002530451	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000162461	SCV002760194	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-14	criteria provided, single submitter	curation	Data included in classification: aGVGD: Class C65 and BayesDel score 0.5 (PP3_mod) 16 entries on cancer hotspots (PM1_mod) Bougeard et al. 2015: ACC in 2 children, Rana et al, 2019: 4 breast cancer cases and 1 sarcoma case, 14 observations in Ambry lab, 6 of which meet Chompret criteria (PS4_str) Data not included in classification: Conflicting functional evidence: Giacomelli et al. Nat Genet. 2018: NO DNE AND NO LOF Kato et al. PNAS 2003: Transactivation Class: non-functional Zerdoumi et al. HMG 2017: Dominant negative effect: ~75% decrease in p53 functionality score of lymphocytes compared to wild-type. Other classifications: Invitae (2020): Pathogenic; Ambry (2020) Counsyl (2016), Color (2015): Likely pathogenic; GeneDx (2019): VUS
CeGaT Center for Human Genetics Tuebingen	RCV000237013	SCV003917884	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	TP53: PM2, PM5, PS4:Moderate
Baylor Genetics	RCV003462117	SCV004206216	pathogenic	Adrenocortical carcinoma, hereditary	2023-10-19	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000430781	SCV000509781	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441098	SCV000509782	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421688	SCV000509783	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431915	SCV000509784	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438666	SCV000509785	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421040	SCV000509786	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433024	SCV000509787	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443535	SCV000509788	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425628	SCV000509789	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432405	SCV000509790	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442735	SCV000509791	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426825	SCV000509792	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436631	SCV000509793	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419372	SCV000509794	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427448	SCV000509795	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438105	SCV000509796	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420028	SCV000509797	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428519	SCV000509798	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439150	SCV000509799	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417610	SCV000509800	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000162461	SCV002589020	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing