ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1040C>A (p.Ala347Asp) (rs397516434)

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Total submissions: 6
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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 2019-08-28 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-segregate 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 uncertain significance Li-Fraumeni syndrome 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 347 of the TP53 protein (p.Ala347Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two unrelated individuals being tested for suspected Li-Fraumeni syndrome. The first individual was affected with high-grade pleomorphic sarcoma at age 19 years, while the second individual was diagnosed with breast cancer at 49 years old. No additional family members were reported to have cancer (PMID: 27501770). This variant was also observed in the IARC TP53 database in a large family affected with cancer, although the specifics of the related cancers were unspecified for many of the family members (PMID: 17311302). ClinVar contains an entry for this variant (Variation ID: 43587). Experimental studies have shown that this missense change affects the ability of TP53 to form a tetramer and transcriptionally transactivate its targets in a yeast-based functional assay (PMID: 16007150, 12826609). In summary, this variant is a rare missense change that has been shown to disrupt TP53 protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Without further genetic data, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000492626 SCV000581153 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-11 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 byin silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255021 SCV000602259 likely pathogenic not provided 2017-03-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036529 SCV000060184 uncertain significance not specified 2008-07-21 no assertion criteria provided clinical testing

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