Submissions for variant NM_000546.6(TP53):c.761TCA[1] (p.Ile255del)

dbSNP: rs1064794309

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483701	SCV000568757	likely pathogenic	not provided	2018-09-20	criteria provided, single submitter	clinical testing	The c.764_766delTCA variant in TP53 gene has previously been reported in at least one individual suspicious for Li-Fraumeni syndrome (Melhem-Bertrandt et al., 2012). The c.764_766delTCA variant is an in-frame deletion that results in the loss of a single Isoleucine residue, denoted p.I255del within the DNA binding domain (Bode et al., 2004). The residue removed by this deletion occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Based on currently available evidence, c.764_766delTCA is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV000525682	SCV000629866	pathogenic	Li-Fraumeni syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This variant, c.764_766del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Ile255del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with TP53-related conditions (PMID: 21761402, 30886117; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.763delATC. ClinVar contains an entry for this variant (Variation ID: 420134). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TP53 function (PMID: 30886117). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV002289630	SCV002582359	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289629	SCV002583019	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289630	SCV002673818	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-17	criteria provided, single submitter	clinical testing	The c.764_766delTCA variant (also known as p.I255del) is located in coding exon 6 of the TP53 gene. This variant results from an in-frame TCA deletion at nucleotide positions 764 to 766. This results in the in-frame deletion of an isoleucine at codon 255. This alteration has been reported as de novo in a proband with bilateral breast cancer at age 32, and also in this individual's child with a high-grade brain tumor diagnosed at age 2 (Quinn E et al. Cold Spring Harb Mol Case Stud 2019 08;5(4)). This alteration has also been identified in an individual with both early-onset breast cancer and astrocytoma (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13). Based on internal structural analysis, p.I255del is considered deleterious to protein structure (Ambry internal data; Golovenko D et al. Structure 2018 09;26(9):1237-1250.e6). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.