Submissions for variant NM_000546.6(TP53):c.749C>T (p.Pro250Leu)

dbSNP: rs1064794311

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479937	SCV000568759	likely pathogenic	not provided	2018-05-09	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.749C>T at the cDNA level, p.Pro250Leu (P250L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has been reported as a somatic variant in osteosarcoma, rhabdomyosarcoma, chronic lymphocytic leukemia, and other tumors and cell lines, but has not been reported as a germline variant to our knowledge (Toguchida 1992, Gokgoz 2001, Pekova 2011, COSMIC). TP53 Pro250Leu is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and has also been described as demonstrating reduced or absent transactivation capabilities in other studies (Campomenosi 2001, Maurici 2001, Monti 2002). In addition, this variant was shown to cause cytoplasmic protein aggregation, resulting in impaired nuclear import and destabilization in HT-1376 bladder cells (Xu 2011). TP53 Pro250Leu was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro250Leu to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547538	SCV000629865	pathogenic	Li-Fraumeni syndrome	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 250 of the TP53 protein (p.Pro250Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 30607672; Invitae). ClinVar contains an entry for this variant (Variation ID: 420136). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21445056, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001026502	SCV001188897	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	The p.P250L pathogenic mutation (also known as c.749C>T), located in coding exon 6 of the TP53 gene, results from a C to T substitution at nucleotide position 749. The proline at codon 250 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of breast cancer diagnosed at age 30 (Bakhuizen JJ et al. Fam Cancer, 2019 Apr;18:273-280). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays. (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9). Additional 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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). This 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000547538	SCV003934642	likely pathogenic	Li-Fraumeni syndrome	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.749C>T (p.Pro250Leu) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD). c.749C>T has been reported in the literature in at least two individuals affected with breast cancer at an early age (diagnosis at < 35 years of age), a clinical feature consistent with Li-Fraumeni Syndrome (e.g. Bakhuizen_2019, George_2021). However, these data do not allow any unequivocal conclusion about association of the variant with Li-Fraumeni Syndrome. The IARC database reports the variant as being non-functional based on overall transcriptional activity on eight different promoters as measured in yeast assays by Kato et al (2003). Additional publications examining the functional effect of the variant report that it results in aggregation and decreased nuclear localization of TP53, reduces transcriptional activity and impairs function compared to the WT protein (e.g. Fischer_2018, Xu_2011, Giacomelli_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30607672, 33646313, 12826609, 30224644, 30089713, 21445056). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.