Submissions for variant NM_000546.6(TP53):c.529_546del (p.Pro177_Cys182del)

dbSNP: rs2073361326

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042929	SCV001206638	pathogenic	Li-Fraumeni syndrome	2024-11-19	criteria provided, single submitter	clinical testing	This variant, c.529_546del, results in the deletion of 6 amino acid(s) of the TP53 protein (p.Pro177_Cys182del), 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 clinical features of TP53-related conditions (PMID: 29489754, 33138793, 33245408). ClinVar contains an entry for this variant (Variation ID: 840834). This variant disrupts a region of the TP53 protein in which other variant(s) (p.Pro177Arg) have been determined to be pathogenic (PMID: 12826609, 20421238, 26787237, 27501770, 27873457, 30224644; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003160297	SCV003856778	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	The c.529_546del18 variant (also known as p.P177_C182del) is located in coding exon 4 of the TP53 gene. This variant results from an in-frame deletion of 18 nucleotides (CCCCACCATGAGCGCTGC) at nucleotide positions 529 to 546. This results in the in-frame deletion of 6 amino acids (PHHERC) at codons 177 to 182. Other variants impacting this region, p.P177R, p.H179Q, p.H179Y, p.E180K have been identified in individuals with features consistent with Li-Fraumeni syndrome (Ambry internal data). This alteration was detected in a cohort of 2538 Chinese breast cancer patients who tested negative for BRCA1/2 mutations (Kwong A et al. BMC Cancer, 2020 Nov;20:1053), as well as in a cohort of 1876 well-defined familial HBOC index patients from Germany who were tested negative for a germline BRCA1/2 mutations (Grill S et al. Arch Gynecol Obstet, 2021 Jun;303:1557-1567). These amino acid positions are generally well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004031305	SCV004933252	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 8336941, 12509279, 17530187]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16633321, 21590121].