ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527123 SCV000629886 uncertain significance Li-Fraumeni syndrome 2018-06-08 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 reported in an individual affected with ovarian cancer (PMID: 19930417). 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 2016-02-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Other data supporting pathogenic classification
Color RCV000561902 SCV000686782 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-17 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.

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