Submissions for variant NM_000546.6(TP53):c.752T>G (p.Ile251Ser)

dbSNP: rs730882027

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161070	SCV000211804	likely pathogenic	not provided	2015-09-23	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.752T>G at the cDNA level, p.Ile251Ser (I251S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC) in exon 7. Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ile251Ser alters a position that is highly conserved among mammals and is located in the DNA binding domain (UniProt). TP53 Ile251Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this variant has not been reported as a germline variant to our knowledge, it has been seen as a somatic mutation in multiple tumor types, including: lymphoid and haemopoietic, breast, ovary, central nervous system, and small intestine (COSMIC). Other published conservative substitutions in the same codon (TP53 p.Ile251Leu and TP53 p.Ile251Met) are considered pathogenic based on reports of association with Li-Fraumeni or Li-Fraumeni-like syndromes and functional analyses showing partial loss of TP53 function (Kato 2003, Monti 2007, Wu 2011, Malcikova 2010, Monti 2011, IARC TP53 database). In silico analyses predict that TP53 Ile251Ser is probably damaging to protein structure and function. Based on the currently available information, we consider TP53 Ile251Ser to be an expected pathogenic variant. Mosaicism for TP53 mutations has been reported in at least three patients, all of whom had cancer themselves and none of whom had a family history significant for Li Fraumeni syndrome (Prochazkova 2009, Walsh 2011, Mitchell 2013). This variant has been seen apparently mosaic. The variant is found in ENDOM-HEREDIC panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003621508	SCV004422456	uncertain significance	Li-Fraumeni syndrome	2022-12-31	criteria provided, single submitter	clinical testing	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. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 251 of the TP53 protein (p.Ile251Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 182967). 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.
Myriad Genetics, Inc.	RCV004019946	SCV004933513	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Ambry Genetics	RCV004019947	SCV005036130	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.I251S pathogenic mutation (also known as c.752T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 752. The isoleucine at codon 251 is replaced by serine, an amino acid with dissimilar 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). 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 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). Two other alterations at the same codon, p.I251L (c.751A>C) and p.I251T (c.752T>C), have been detected in families with features of Li Fraumeni syndrome (Ambry internal data; Wu CC et al. Hum. Genet. 2011 Jun; 129(6):663-73). 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.