Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV000824076 | SCV007449439 | pathogenic | Li-Fraumeni syndrome | 2024-05-23 | criteria provided, single submitter | clinical testing | Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_Supporting). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2). |
| Center for Genomic Medicine, |
RCV006273737 | SCV007129835 | likely oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002289523 | SCV002678210 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-12-13 | criteria provided, single submitter | clinical testing | The p.F270S pathogenic mutation (also known as c.809T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 809. The phenylalanine at codon 270 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been observed as de novo in an individual with TP53-associated disease (Ambry internal data). 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). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (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. 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. |
| Genome- |
RCV002289522 | SCV002583014 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002289523 | SCV002582353 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000824076 | SCV000964957 | pathogenic | Li-Fraumeni syndrome | 2025-05-13 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 270 of the TP53 protein (p.Phe270Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TP53-related disease (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376594). Invitae Evidence Modeling incorporating data from in vitro 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: 9979965, 12826609, 12917626, 30224644). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000481465 | SCV000572280 | likely pathogenic | not provided | 2018-08-21 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.809T>C at the cDNA level, p.Phe270Ser (F270S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). TP53 Phe270Ser has not, to our knowledge, been published as a germline pathogenic or benign variant, however it has been observed as a somatic variant in several different tumor types, including colorectal, endometrial, pancreatic, and breast (Nyiraneza 2011, McConechy 2012, Forbes 2015). This variant 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 also showed defective transactivation and growth suppression in other assays, but no dominant-negative effect (Marutani 1999, Monti 2003, Kotler 2018). TP53 Phe270Ser 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 currently available information, we consider TP53 Phe270Ser to be a likely pathogenic variant. |