ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.329G>A (p.Arg110His) (rs11540654)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115719 SCV000184511 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115719 SCV000902812 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000409407 SCV000488218 uncertain significance Li-Fraumeni syndrome 1 2016-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000589869 SCV000149628 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted TP53 c.329G>A at the cDNA level, p.Arg110His (R110H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been observed in at least three individuals with breast cancer (Rath 2013, Tung 2016, Hauke 2018). TP53 Arg110His was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and other functional studies have revealed growth suppression and apoptotic activities comparable to wild-type (Bergamaschi 2003, Kotler 2018). TP53 Arg110His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether TP53 Arg110His is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000122182 SCV000086399 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000589869 SCV000697440 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing
Invitae RCV000228299 SCV000285188 uncertain significance Li-Fraumeni syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 110 of the TP53 protein (p.Arg110His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs11540654, ExAC 0.03%). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 23580068). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 127808). Experimental in vitro studies have shown that this missense change causes a very small effect on cellular sensitivity to cisplastin-induced apoptosis (PMID: 12726864) and partially affects the transcriptional transactivation function of the TP53 protein (PMID: 12826609). The clinical significance of these results is unknown. 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.
True Health Diagnostics RCV000115719 SCV000886720 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 no assertion criteria provided clinical testing

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