Submissions for variant NM_000546.6(TP53):c.1040C>A (p.Ala347Asp)

dbSNP: rs397516434

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000468537	SCV001142526	likely pathogenic	Li-Fraumeni syndrome	2022-03-18	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a low functioning allele according to Kato, et al. and there is a tetramerization assay demonstrating a mutant protein that only forms dimers (PS3; PMID: 12826609, PMID: 16007150). This variant has been reported in 1 proband meeting Classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 27496084). The variant was found to co-segregation with disease in this proband’s family, with 5 or 6 meioses observed (PP1_Moderate; PMID: 27496084). In summary, TP53 c.1040C>A; p.Ala347Asp 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, PS3, PS4_Supporting, PP1_Moderate.
GeneDx	RCV000255021	SCV000321974	pathogenic	not provided	2021-03-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of tetramer formation, non-functional transactivation, and reduced growth suppression activity (Kato 2003, Kawaguchi 2005, Fischer 2018) Identified in individuals with Li-Fraumeni syndrome referred for genetic testing at GeneDx and in published literature, segregating with disease in multiple affected individuals from a single family (Villani 2016) Not observed in large population cohorts (Lek 2016) In silico analysis supports that this missense variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 29955864, 26447779, 27496084, 27501770, 27834926, 26572807, 16007150, 12826609)
Invitae	RCV000468537	SCV000545289	pathogenic	Li-Fraumeni syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 347 of the TP53 protein (p.Ala347Asp). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 27501770, 32817165, Invitae), and has been reported in individuals in the IARC TP53 database (PMID: 27328919). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43587). 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: 12826609, 16007150, 29955864). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492626	SCV000581153	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	The p.A347D variant (also known as c.1040C>A), located in coding exon 9 of the TP53 gene, results from a C to A substitution at nucleotide position 1040. The alanine at codon 347 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in two individuals from a cohort of 89 carriers of TP53 pathogenic variants; a female patient with a high-grade pleomorphic sarcoma at age 19, and a female patient with breast cancer and a cardiac sarcoma at ages 49 and 57 respectively (Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305). This alteration occurs in the hydrophobic alpha-helix domain of the p53 protein, and was found to be transcriptionally inactive in one study (Kawaguchi T et al. Oncogene. 2005 Oct 20;24(46):6976-81), and was shown to have a loss of transactivation capacity in an additional yeast-based functional study (Kato S et al. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9). Further, an alteration at this same location, p.A347T (c.1039G>A), has been reported in an individual diagnosed with breast cancer under the age of 50 (Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444), has shown partially reduced transactivation capacity in a yeast-based functional assay (Kato S et al. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9), and has been shown to result in the inability of the p53 protein to form tetramers in a structural studies (Kawaguchi T et al. Oncogene. 2005 Oct;24:6976-81; Kamada R et al. J. Biol. Chem. 2011 Jan;286:252-8). This amino acid position is well 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255021	SCV000602259	likely pathogenic	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315555	SCV004018680	likely pathogenic	Li-Fraumeni syndrome 1	2023-06-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 37067911, 34881245, 16007150]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 27501770, 28772286, 37067911].
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036529	SCV000060184	uncertain significance	not specified	2008-07-21	no assertion criteria provided	clinical testing