ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.467G>A (p.Arg156His) (rs371524413)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115722 SCV000186315 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CSER_CC_NCGL; University of Washington Medical Center RCV000148908 SCV000190654 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research
Color RCV000115722 SCV000911005 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000656987 SCV000149631 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.467G>A at the cDNA level, p.Arg156His (R156H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Although this variant has been reported in at least two individuals with multiple Li-Fraumeni spectrum tumors, both had other TP53 variants identified as well, making it difficult to assess the individual contribution of TP53 Arg156His to their phenotype (Quesnel 1999, DiNardo 2016). This variant was also observed in a woman with early-onset bilateral breast cancer (Heymann 2010) and a teenage patient with adrenocortical carcinoma (Juhlin 2015). On functional interrogation TP53 Arg156His was not found to impact transcriptional activation or growth suppression (Quesnel 1999, Monti 2011) and 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). TP53 Arg156His was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg156His 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 Arg156His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000148908 SCV000218877 uncertain significance Li-Fraumeni syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 156 of the TP53 protein (p.Arg156His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371524413, ExAC 0.006%). This variant was reported in individuals affected with Li-Fraumeni syndrome (LFS) (PMID: 9667734, 10435620, 26086041, 21343334), an individual affected with fibrolamellar hepatocellular carcinoma and this individual's unaffected mother (PMID: 28477317), an individual with colon cancer (PMID: 30092803), and an individual affected with rhabdomyosarcoma and therapy-related acute myeloid leukemia (PMID: 27210295). However, in some of these individuals (PMID: 21343334, 27210295, 26086041, 10435620, 9667734), additional missense variants were identified in the TP53 gene, making it challenging to determine the relative contribution of the p.Arg156His missense change to the phenotype. ClinVar contains an entry for this variant (Variation ID: 127811). Functional studies have shown that this variant does not affect transcriptional activation or cell proliferation arrest, but does cause decreased expression levels relative to the wild-type protein (PMID: 10435620, 21343334, 17606709, 17311302). 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.
Mendelics RCV000148908 SCV000839119 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213052 SCV000602272 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing

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