Submissions for variant NM_000546.6(TP53):c.884C>T (p.Pro295Leu)

gnomAD frequency: 0.00001  dbSNP: rs751713111

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486525	SCV000570029	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.884C>T at the cDNA level, p.Pro295Leu (P295L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). While this variant has been reported in breast tissue, it has not, to our knowledge, been reported in the literature as a pathogenic or benign germline variant (Al-Qasem 2011). TP53 Pro295Leu is reported as having ?super? transactivation function (transactivation capacities >100% for multiple reporters) in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Pro295Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Pro295Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633374	SCV000754596	uncertain significance	Li-Fraumeni syndrome	2024-12-23	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 295 of the TP53 protein (p.Pro295Leu). This variant is present in population databases (rs751713111, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30982232). ClinVar contains an entry for this variant (Variation ID: 420974). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000774786	SCV000908784	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 295 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Expermental studies have demonstrated this variant to be functional in yeast transcriptional transactivation assays (PMID: 12826609) but inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 30212483, 30982232, 33471991), bit also in healthy individuals (PMID: 33471991), and several of these breast cancer cases co-occurred with BRCA1 truncations (PMID: 30982232). This variant has been identified in 6/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000774786	SCV001179643	likely benign	Hereditary cancer-predisposing syndrome	2019-08-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV000633374	SCV004823754	uncertain significance	Li-Fraumeni syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 295 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Expermental studies have demonstrated this variant to be functional in yeast transcriptional transactivation assays (PMID: 12826609) but inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 30212483, 30982232, 33471991), bit also in healthy individuals (PMID: 33471991), and several of these breast cancer cases co-occurred with BRCA1 truncations (PMID: 30982232). This variant has been identified in 6/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.