Submissions for variant NM_000546.6(TP53):c.754_762del (p.Leu252_Ile254del)

dbSNP: rs2073243450

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046315	SCV001210212	pathogenic	Li-Fraumeni syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This variant, c.754_762del, results in the deletion of 3 amino acid(s) of the TP53 protein (p.Leu252_Ile254del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TP53 protein in which other variant(s) (p.Ile254Asn) have been determined to be pathogenic (PMID: 17724467, 29070607). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 843641). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002393228	SCV002672046	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	The c.754_762delCTCACCATC variant (also known as p.L252_I254del) is located in coding exon 6 of the TP53 gene. This variant results from an in-frame CTCACCATC deletion at nucleotide positions 754 to 762, and a deletion of 3 amino acids from 252 to 254. This amino acid region is well conserved in available vertebrate species. This alteration was identified in a patient with TP53 related tumors (Bougeard G et al. J Med Genet, 2008 Aug;45:535-8). Based on internal structural analysis, L252_I254del disrupts the sensitive DNA-binding domain of TP53 to a higher degree than nearby pathogenic variants (Golovenko D et al. Structure, 2018 09;26:1237-1250.e6). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004031432	SCV004931480	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].