Submissions for variant NM_000546.6(TP53):c.380C>T (p.Ser127Phe)

dbSNP: rs730881999

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161024	SCV000211743	pathogenic	not provided	2021-10-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced transcriptional activation for multiple p53 response elements, loss of growth suppression activity, non-functional transactivation (Kato 2003, Dekairelle 2005, Bally 2015, Kotler 2018); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx in published literature (Guindalini 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25308272, 30312528, 16322298, 16000567, 24280411, 25033756, 21747090, 26271412, 15195137, 16094622, 12826609, 29085664, 29979965, 30154229, 15510160)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606528	SCV000712629	uncertain significance	not specified	2016-11-22	criteria provided, single submitter	clinical testing	The p.Ser127Phe variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. Computational predicti on tools and conservation analysis suggest that the p.Ser127Phe variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Ser127Phe variant is uncertain.
Invitae	RCV000633384	SCV000754606	pathogenic	Li-Fraumeni syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 127 of the TP53 protein (p.Ser127Phe). 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 and/or Li-Fraumeni syndrome (PMID: 32817165, 34240179; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182928). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16000567, 16322298, 29979965, 30224644). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; 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.
Mendelics	RCV000606528	SCV002516106	likely pathogenic	not specified	2023-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162681	SCV003878902	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The p.S127F variant (also known as c.380C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 380. The serine at codon 127 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in a cohort of 295 women considered at high risk for breast cancer (Guindalini RSC et al. Clin Cancer Res, 2019 Mar;25:1786-1794). 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 U S A, 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). Another alteration at the same codon, p.S127T (c.379T>A), has been shown to also have non-functional transactivation in yeast based assays, be deficient at growth suppression, and have a dominant negative effect (Ambry internal data; 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). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003474836	SCV004204273	likely pathogenic	Adrenocortical carcinoma, hereditary	2022-09-21	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785332	SCV000923900	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
University Health Network, Princess Margaret Cancer Centre	RCV000785332	SCV001738483	pathogenic	Neoplasm of ovary	2021-03-19	no assertion criteria provided	clinical testing