Submissions for variant NM_000546.6(TP53):c.569CTC[1] (p.Pro191del)

dbSNP: rs1555525902

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557025	SCV000629843	pathogenic	Li-Fraumeni syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This variant, c.572_574del, results in the deletion of 1 amino acid(s) of the TP53 protein (p.Pro191del), 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 individuals with clinical features of Li-Fraumeni syndrome (PMID: 33245408; external communication, internal data). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TP53 function (PMID: 33116240). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001024453	SCV001186472	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-01-28	criteria provided, single submitter	clinical testing	The c.572_574delCTC variant (also known as p.P191del) is located in coding exon 5 of the TP53 gene. This variant results from an in-frame CTC deletion at nucleotide positions 572 to 574. This results in the in-frame deletion of a proline at codon 191. This alteration has been reported in an individual meeting Chompret criteria (Grill S et al. Arch Gynecol Obstet, 2020 Nov) and has also been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data, personal communication). This alteration has also been reported in the tumor of an individual with adrenocortical carcinoma (Barzon L et al. Eur. J. Endocrinol., 2001 Aug;145:207-12). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast and human cell assays (Monti P et al. Sci Rep, 2020 10;10:18427). Based on internal structural assessment, this alteration results in disruption of the DNA-binding domain (Ambry internal data). This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV001576499	SCV001803704	likely pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of transactivation activity (Monti 2020); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33116240, 28522256, 30185652, 29805648, 29489027, 30041611, 27407063, 25313908, 22983585, 21483000, 26425688, 26205736, 27045317, 27586204, 11454518, 31317311)
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760557	SCV005373783	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	curation	According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS4 (supporting pathogenic): Multiple Individuals meeting chompret criteria, PM2 (supporting pathogenic): not in gnomAD