Submissions for variant NM_000546.6(TP53):c.917G>A (p.Arg306Gln)

dbSNP: rs1048095040

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527123	SCV000629886	uncertain significance	Li-Fraumeni syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 306 of the TP53 protein (p.Arg306Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, appendiceal adenocarcinoma, and/or lung cancer (PMID: 19930417, 30374176, 35033608). ClinVar contains an entry for this variant (Variation ID: 458574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 30224644). 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.
Ambry Genetics	RCV000561902	SCV000664396	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-23	criteria provided, single submitter	clinical testing	The p.R306Q variant (also known as c.917G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 917. The arginine at codon 306 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an ovarian cancer patient and in a pediatric AML patient (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6; Fenwarth L et al. Haematologica, 2021 03;106:908-912). This variant was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was classified as likely benign by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant is reported to have non-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 proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000561902	SCV000686782	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 306 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that the variant impairs the transactivation activity of the TP53 protein (PMID: 12826609 and IARC database). This variant has been reported in an individual affected with ovarian cancer (PMID: 19930417). This variant has also been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000527123	SCV000788228	likely benign	Li-Fraumeni syndrome	2018-03-28	criteria provided, single submitter	research	The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as likely benign in the context of Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.05 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. The variant is at a moderately conserved genomic position. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. However, loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in this observed family, which provides some evidence for pathogenicity with regard to the individual's breast cancer. We cannot rule out the possibility that this variant may cause some increased risk for breast cancer or other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664300	SCV000788229	uncertain significance	Familial cancer of breast	2017-06-13	criteria provided, single submitter	research	The TP53 variant designated as NM_000546.5:c.917G>A (p.Arg306Gln) is classified as variant of uncertain significance in the context of famiial breast cancer. Loss of heterozygosity was seen in the tumor of an affected individual with breast cancer in one family, which provides evidence for pathogenicity. Some TP53 missense variants have been associated with somewhat increased risk of breast cancer, but do not cause the high cancer risk associated with truncating TP53 variants (Giacomazzi et al., 2014, PMID:24936644; Arcand et al., 2015, PMID:25925845; Zick et al., 2016, PMID:27866339). Exact breast cancer penetrance for these variants has not been established. For the TP53 p.Arg306Gln variant, family co-segregation analysis assuming low penetrance gives a likelihood ratio of 0.34 using the Thompson et al. cosegregation method (PMID:12900794). This likelihood ratio is less than one, indicating that the variant is less likely to be associated with breast cancer risk. The TP53 p.Arg306Gln variant has not previously been reported in ClinVar. It is at a moderately conserved genomic position. A modest increase in breast cancer risk due to this variant cannot be entirely excluded. This variant is considered a variant of uncertain significance in the context of breast cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986056	SCV001134880	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 19930417 (2010)). Experimental results on protein function were inconclusive (PMIDs: 30352134 (2019), 30224644 (2018), 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000989706	SCV001140245	uncertain significance	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000986056	SCV002601159	uncertain significance	not provided	2024-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 25490678, 19930417, 30374176, 30352134, 25925845, 35033608, 30224644, 27866339, 34273903, 35534704, 33471991, 32554555)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330753	SCV004039177	uncertain significance	not specified	2023-08-23	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.917G>A (p.Arg306Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes (gnomAD). c.917G>A has been reported in the literature in individuals affected breast- and ovarian cancer (e.g. Blanco_2010, Tsai_2019), and with various tumor phenotypes that belong to the Li-Fraumeni Syndrome tumor spectrum (e.g. Fenwarth_2020, Tian_2022), however it was also reported in unaffected controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC TP53 database reports this variant to be non- functional based on transcriptional activity in yeast (Kato_2003). However, a loss-of-function saturation mutagenesis screen performed in in human cell lines indicated that this missense doesn't substantially affect TP53 function (Giacomelli_2018). In addition, a multifactorial probability model predicted this variant to be a VUS (Fortuno_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19930417, 30374176, 32554555, 33471991, 35033608, 12826609, 30224644, 34273903). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000527123	SCV004823750	uncertain significance	Li-Fraumeni syndrome	2023-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 306 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that the variant impairs the transactivation activity of the TP53 protein (PMID: 12826609 and IARC database). This variant has been reported in an individual affected with ovarian cancer (PMID: 19930417). This variant has also been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004568752	SCV005054349	uncertain significance	Adrenocortical carcinoma, hereditary	2023-12-07	criteria provided, single submitter	clinical testing