Submissions for variant NM_000546.6(TP53):c.537T>A (p.His179Gln)

dbSNP: rs876660821

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000464573	SCV001142545	pathogenic	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Additionally, there was a de novo observation in an individual with two Li-Fraumeni syndrome spectrum tumors under the age of 5 years without mention of maternal confirmation (PM6; PMID: 19556618). In summary, TP53 c.537T>A; p.His179Gln meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PS3, PM1, PM6.
Invitae	RCV000464573	SCV000545303	pathogenic	Li-Fraumeni syndrome	2022-12-24	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Li-Fraumeni syndrome and follicular lymphoma (PMID: 18628487, 19556618). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16209708, 17311302, 22540896, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 406578). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Gln).
Ambry Genetics	RCV000567952	SCV000664423	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-09	criteria provided, single submitter	clinical testing	The p.H179Q pathogenic mutation (also known as c.537T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 537. The histidine at codon 179 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in a kindred meeting Chompret crieria for Li-Fraumeni syndrome (LFS) (Gonzalez KD et al. J. Med. Genet. 2009 Oct;46:689-93). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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 (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The amino acid residue altered by this variant has been shown to be functionally important for zinc binding, and alterations affecting this amino acid have been associated with poorer prognosis in breast cancer patients (Martin AC et al. Hum. Mutat. 2002 Feb;19:149-64; Olivier M et al. Clin. Cancer Res. 2006 Feb;12:1157-67). Another amino acid change at this codon (p.H179Y) has been reported as pathogenic in multiple cases and functional studies (Wasserman JD et al. J. Clin. Oncol. 2015 Feb 20;33(6):602-9; Pan Y et al. Nucleic Acids Res. 2014 Oct;42(18):11570-88), and a different alteration leading to this same amino acid substitution [p.H179Q (c.537T>G)] has been reported in a French family with a clinical history suggestive of Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8), and in a woman with breast cancer at age 27 (Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
University Health Network, Princess Margaret Cancer Centre	RCV001527472	SCV001738489	pathogenic	Neoplasm of ovary	2021-03-19	no assertion criteria provided	clinical testing
Hematological Lab, University of Education	RCV003159559	SCV003853554	pathogenic	Acute myeloid leukemia		no assertion criteria provided	clinical testing