Submissions for variant NM_000546.6(TP53):c.535C>A (p.His179Asn)

dbSNP: rs587780070

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564826	SCV000665284	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-22	criteria provided, single submitter	clinical testing	The p.H179N variant (also known as c.535C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 535. The histidine at codon 179 is replaced by asparagine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 is one of four amino acid residues required for zinc binding and protein stabilization (Martin et al Hum. Mutat. 2002 Feb;19(2):149-64). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695193	SCV000823676	uncertain significance	Li-Fraumeni syndrome	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 376609). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8633021, 9290701, 10616528, 12826609, 16861262, 19462533, 29979965). 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.
GeneDx	RCV001575036	SCV001801947	likely pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of growth suppression and DNA binding, partial or absent transactivation activities, and causes as a dominant-negative effect (Brachmann 1996, Kato 2003, Dearth 2007, Ahn 2009, Kotler 2018, Giacomelli 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 30089713, 31262012, 11238194, 30224644, 27813088, 12826609, 26619011, 29979965, 26536055, 25695693, 10616528, 14559903, 9290701, 19462533, 23117049, 18725321, 26723900, 15161705, 10754498, 16861262, 8633021)
Myriad Genetics, Inc.	RCV004022218	SCV004931470	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27813088, 19462533]. This variant is expected to disrupt protein structure [Myriad internal data].