ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.917G>A (p.Arg306Gln) (rs1048095040)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527123 SCV000629886 uncertain significance Li-Fraumeni syndrome 2020-02-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 306 of the TP53 protein (p.Arg306Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with ovarian cancer (PMID: 19930417) and breast cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 458574). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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 2018-12-20 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 as a somatic mutation twice in various tumors, once as a germline mutation by the the IARC TP53 database, and is reported to have loss of transactivation capacity (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This alteration has been reported in an ovarian cancer patient with a family history of breast cancer who previously tested negative for mutations in the BRCA1/2 genes (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6). 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 Health, Inc RCV000561902 SCV000686782 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-21 criteria provided, single submitter clinical testing
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 2019-07-08 criteria provided, single submitter clinical testing
Mendelics RCV000989706 SCV001140245 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing

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